Antibody capable of specifically recognizing factor XIIa and application thereof

Abstract

The present invention relates to antibodies or antigen binding fragments that specifically recognize Factor XIIa, methods of making and uses thereof.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the priority of Chinese patent application with patent application number 202310717526.0, application date 2023.06.16, and invention name “Antibodies specifically recognizing Factor XIIa and their applications”, and the entire contents of the application are incorporated herein by reference.

[0003] Submit sequence listing as XML text file

[0004] The contents of the electronic sequence listing are incorporated herein by reference in their entirety: (FXIIa-M-WIPO seq.xml; size: 100 KB; and creation date: 2023.06.14. Technical Field

[0005] The present invention relates to an antibody that specifically recognizes FXIIa, and a preparation method and use thereof, including using the antibody to treat thrombosis, diseases related to FXII / FXIIa-induced kinin formation, diseases related to FXII / FXIIa-induced complement activation, diseases related to the contact activation system, and diseases related to inflammation. Background Art

[0006] Factor XII (FXII) is an 80 kDa glycoprotein with a plasma concentration of approximately 40 μg / mL (approximately 500 nmol / L). FXII in plasma is mainly synthesized in the liver. FXII plays a role in activating the intrinsic pathway of coagulation and the kallikrein-kinin system. FXII undergoes auto-activation by exposure to negatively charged surfaces (e.g., polyanionic surfaces, glass, polyphosphates, ellagic acid, etc.) to produce the active form FXIIa. Activated FXIIa can cleave plasma prekallikrein (PK) to produce active plasma kallikrein (pKal); subsequently, activated pKal can cleave FXII into FXIIa; the formed FXIIa activates more PK and produces more pKal, thus forming a positive feedback loop and amplification effect.

[0007] Activated FXIIa consists of a heavy chain and a light chain, which are connected by a disulfide bond. The heavy chain contains the following domains: fibronectin type II domain, epidermal growth factor (EGF)-like domain I, fibronectin type I domain, epidermal growth factor-like domain II, kringle domain, and proline-rich domain, which is unique to FXII. The heavy chain contains a region that binds to a negatively charged surface, and the light chain contains a catalytic domain typical of serine proteases, so FXII has a domain composition similar to other members of the serine protease family. The active site on the FXII light chain consists of typical catalytic triad residues His40, Asp89, and Ser191. This site is also the target of C1 esterase inhibitor (C1-INH), the main intrinsic inhibitor of the coagulation pathway. Cleavage or autologous activation by kallikrein leads to the cleavage of Arg353-Val354 bound to the FXII zymogen, forming α-FXIIa (α-FXIIa), which contains a heavy chain and a light chain connected by a disulfide bond. Two additional peptide bonds in the α-FXIIa form generate 30 kD β-FXIIa under the action of, for example, trypsin, containing a complete light chain and a truncated fragment of the heavy chain. α-FXIIa is able to bind to negatively charged surfaces and activate FXI and PK. β-FXIIa has no surface binding ability but can activate PK.

[0008] FXII deficiency, known as the Hageman trait, was first identified by Oscar Ratnoff as a defect that results in prolonged surface-activated blood coagulation tests such as the partial thromboplastin time (PTT) (Ratnoff et al., 1955, J Clin Invest, 34: 602-13.). Earl Davie was the first to purify Hageman factor and named it factor XII according to convention. He and Ratnoff first demonstrated that FXII activates the plasma thrombin precursor FXI, and later demonstrated that FXIa activates FIX (Ratnoff et al., 1961, J Clin Invest, 40: 803-19; Ratnoff et al., 1962, Biochemistry, 1: 677-85.). These results were the basis for the coagulation cascade hypothesis they proposed at the same time as RG MacFarland, and were also the basis for the contact activation hypothesis that initiates blood coagulation. It is known that the deficiency of coagulation factor XII is not associated with increased spontaneous or injury-related bleeding complications, but the deficiency of FXII is associated with an increased risk of venous thrombosis (Kuhli C et al., 2004, Am J Ophthalmol, 137: 459-464; Halbmayer WM et al., 1993, Wien Med Wochenschr. 143: 43-50). Subsequent studies have also shown that FXII-deficient mice do not undergo spontaneous or excessive injury-related bleeding, but are protected from collagen- and adrenaline-induced thromboembolism, and that infusion of human FXII into FXII-deficient mice can restore injury-induced thrombosis (Renne T et al., 2005, J Exp Med; 202(2): 271–281). These results suggest that FXII plays an important role in the pathological thrombosis process, and therefore interfering with or blocking FXII activity may be suitable for blocking pathogenic arterial thrombosis and its clinical consequences.

[0009] FXII not only plays a role in the intrinsic coagulation pathway, but pKal formed by FXIIa activation or other means can initiate the kallikrein-kinin system. pKal cleaves high molecular weight kininogen (HK) to release bradykinin and kininogen fragments (i.e., cHK). Bradykinin affects vascular permeability by binding to G protein-coupled receptor bradykinin B2 and B1 receptors. C1-INH, as the main inhibitor of FXIIa and pKal, regulates the contact activation system. Insufficient plasma levels or abnormal function of C1-INH cause continuous activation of FXIIa and pKal, leading to increased bradykinin formation (Caccia et al., 2014, Pediatr Allergy Immunol Pulmonol.; 27(4):159–163). The hereditary angioedema (HAE) syndromes are a group of disorders caused by a lack or deficiency of C1-INH (most commonly types I and II), or by a gain of function of FXIIa (type III), plasmin, or angiopoietin 1 (Bafunno V et al., 2018, J Allergy Clin Immunol;141:1009–17.). In type I HAE with C1-INH deficiency, neither FXIIa nor pKal are adequately inhibited, leading to enhanced bradykinin production and, thus, increased vascular permeability. To date, all of these different mechanisms, with the exception of the gain-of-function angiopoietin I mechanism, result in increased local bradykinin delivery to tissues, which causes vasodilation, increased vascular permeability, and angioedema (Caccia et al., 2014, Pediatr Allergy Immunol Pulmonol.;27(4):159–163). Blockade of the bradykinin B2 receptor alleviates symptoms in many patients with HAE. Importantly, inhibition of the active enzyme of the contact-activated system by injection of C1-INH replacement products or inhibition of pKal by monoclonal antibodies or non-peptide mimetics can also improve and prevent type I and type II HAE in most patients (Banerji et al., 2018, JAMA, 320:2108–21; -Pürsün E et al., 2018, N Engl J Med; 379:352–62.).

[0010] Patent application WO2013014092A1 discloses an anti-FXII / FXIIa monoclonal antibody or an antigen-binding fragment thereof, the binding affinity of the antibody to human FXIIa-β is more than twice that to human FXII, and can inhibit the amide cleavage activity of human FXIIa. Patent application WO2017015431A1 discloses an anti-FXIIa antibody and a method for using the anti-FXII antibody to treat diseases related to FXII.

[0011] There remains a need in the art for therapeutic antibodies that effectively inhibit or otherwise antagonize FXII, and related methods for treating diseases or conditions mediated by FXII, such as thrombosis, diseases associated with FXII / FXIIa-induced kinin formation, diseases associated with FXII / FXIIa-induced complement activation, and diseases associated with the contact activation system.

[0012] The disclosures of all publications, patents, patent applications, and published patent applications mentioned herein are incorporated by reference in their entirety.

[0013] Application Overview

[0014] In some embodiments, an isolated anti-FXIIa antibody is provided, comprising: (i) V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 10, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 22; and V L , the V L It comprises: LC-CDR1, which comprises the amino acid sequence of SEQ ID NO:34, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:48, and LC-CDR3, which comprises the amino acid sequence of SEQ ID NO:56.

[0015] In some embodiments, any one of the isolated anti-FXIIa antibodies described above comprises: V H , comprising the amino acid sequence shown in SEQ ID NO: 73 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO: 73; and V L , which comprises the amino acid sequence shown in SEQ ID NO:90 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO:90.

[0016] In some embodiments, an isolated anti-FXIIa antibody is provided, comprising: (i) V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 11, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 23; and V L , the V LIt comprises: LC-CDR1, which comprises the amino acid sequence of SEQ ID NO:35, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:49, and LC-CDR3, which comprises the amino acid sequence of SEQ ID NO:57.

[0017] In some embodiments, any one of the isolated anti-FXIIa antibodies described above comprises: V H , comprising the amino acid sequence shown in SEQ ID NO: 74 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO: 74; and V L , which comprises the amino acid sequence shown in SEQ ID NO:91 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO:91.

[0018] In some embodiments, an isolated anti-FXIIa antibody is provided, comprising: (i) V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 2, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 12, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 24; and V L , the V L It comprises: LC-CDR1, which comprises the amino acid sequence of SEQ ID NO:36, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:50, and LC-CDR3, which comprises the amino acid sequence of SEQ ID NO:58.

[0019] In some embodiments, any one of the isolated anti-FXIIa antibodies described above comprises: V H , comprising the amino acid sequence shown in SEQ ID NO: 75 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO: 75; and V L , which comprises the amino acid sequence shown in SEQ ID NO:92 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO:92.

[0020] In some embodiments, an isolated anti-FXIIa antibody is provided, comprising: (i) V H , the V Hcomprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 3, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 13, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 25; and V L , the V L It comprises: LC-CDR1, which comprises the amino acid sequence of SEQ ID NO:37, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:51, and LC-CDR3, which comprises the amino acid sequence of SEQ ID NO:59.

[0021] In some embodiments, any one of the isolated anti-FXIIa antibodies described above comprises: V H , comprising the amino acid sequence shown in SEQ ID NO: 76 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO: 76; and V L , which comprises the amino acid sequence shown in SEQ ID NO:93 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO:93.

[0022] In some embodiments, an isolated anti-FXIIa antibody is provided, comprising: (i) V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 4, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 14, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 26; and V L , the V L It comprises: LC-CDR1, which comprises the amino acid sequence of SEQ ID NO:37, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:51, and LC-CDR3, which comprises the amino acid sequence of SEQ ID NO:60.

[0023] In some embodiments, any one of the isolated anti-FXIIa antibodies described above comprises: V H , comprising the amino acid sequence shown in SEQ ID NO: 77 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO: 77; and V L , which comprises the amino acid sequence shown in SEQ ID NO:94 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO:94.

[0024] In some embodiments, an isolated anti-FXIIa antibody is provided, comprising: (i) V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 3, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 13, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 25; and V L , the V L It comprises: LC-CDR1, which comprises the amino acid sequence of SEQ ID NO:37, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:51, and LC-CDR3, which comprises the amino acid sequence of SEQ ID NO:61.

[0025] In some embodiments, any one of the isolated anti-FXIIa antibodies described above comprises: V H , comprising the amino acid sequence shown in SEQ ID NO: 78 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO: 78; and V L , which comprises the amino acid sequence shown in SEQ ID NO:95 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO:95.

[0026] In some embodiments, an isolated anti-FXIIa antibody is provided, comprising: (i) V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 2, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 12, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 24; and V L , the V L It comprises: LC-CDR1, which comprises the amino acid sequence of SEQ ID NO:38, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:50, and LC-CDR3, which comprises the amino acid sequence of SEQ ID NO:62.

[0027] In some embodiments, any one of the isolated anti-FXIIa antibodies described above comprises: V H , comprising the amino acid sequence shown in SEQ ID NO: 79 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO: 79; and V L, which comprises the amino acid sequence shown in SEQ ID NO:96 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO:96.

[0028] In some embodiments, an isolated anti-FXIIa antibody is provided, comprising: (i) V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 3, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 13, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 25; and V L , the V L It comprises: LC-CDR1, which comprises the amino acid sequence of SEQ ID NO:39, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:52, and LC-CDR3, which comprises the amino acid sequence of SEQ ID NO:63.

[0029] In some embodiments, any one of the isolated anti-FXIIa antibodies described above comprises: V H , comprising the amino acid sequence shown in SEQ ID NO: 80 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO: 80; and V L , which comprises the amino acid sequence shown in SEQ ID NO:97 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO:97.

[0030] In some embodiments, an isolated anti-FXIIa antibody is provided, comprising: (i) V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 10, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 27; and V L , the V L It comprises: LC-CDR1, which comprises the amino acid sequence of SEQ ID NO:40, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:53, and LC-CDR3, which comprises the amino acid sequence of SEQ ID NO:64.

[0031] In some embodiments, any one of the isolated anti-FXIIa antibodies described above comprises: V H, comprising the amino acid sequence shown in SEQ ID NO: 81 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO: 81; and V L , which comprises the amino acid sequence shown in SEQ ID NO:98 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO:98.

[0032] In some embodiments, an isolated anti-FXIIa antibody is provided, comprising: (i) V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 5, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 15, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 28; and V L , the V L It comprises: LC-CDR1, which comprises the amino acid sequence of SEQ ID NO:41, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:50, and LC-CDR3, which comprises the amino acid sequence of SEQ ID NO:65.

[0033] In some embodiments, any one of the isolated anti-FXIIa antibodies described above comprises: V H , comprising the amino acid sequence shown in SEQ ID NO: 82 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO: 82; and V L , which comprises the amino acid sequence shown in SEQ ID NO:99 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO:99.

[0034] In some embodiments, an isolated anti-FXIIa antibody is provided, comprising: (i) V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 6, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 16, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 29; and V L , the V L It comprises: LC-CDR1, which comprises the amino acid sequence of SEQ ID NO:42, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:54, and LC-CDR3, which comprises the amino acid sequence of SEQ ID NO:66.

[0035] In some embodiments, any one of the isolated anti-FXIIa antibodies described above comprises: V H , comprising the amino acid sequence shown in SEQ ID NO: 83 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO: 83; and V L , which comprises the amino acid sequence shown in SEQ ID NO: 100 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO: 100.

[0036] In some embodiments, an isolated anti-FXIIa antibody is provided, comprising: (i) V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 6, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 17, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 30; and V L , the V L It comprises: LC-CDR1, which comprises the amino acid sequence of SEQ ID NO:43, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:50, and LC-CDR3, which comprises the amino acid sequence of SEQ ID NO:67.

[0037] In some embodiments, any one of the isolated anti-FXIIa antibodies described above comprises: V H , comprising the amino acid sequence shown in SEQ ID NO: 84 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO: 84; and V L , which comprises the amino acid sequence shown in SEQ ID NO:101 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO:101.

[0038] In some embodiments, an isolated anti-FXIIa antibody is provided, comprising: (i) V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 5, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 15, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 28; and V L , the V LIt comprises: LC-CDR1, which comprises the amino acid sequence of SEQ ID NO:44, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:50, and LC-CDR3, which comprises the amino acid sequence of SEQ ID NO:68.

[0039] In some embodiments, any one of the isolated anti-FXIIa antibodies described above comprises: V H , comprising the amino acid sequence shown in SEQ ID NO: 85 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO: 85; and V L , which comprises the amino acid sequence shown in SEQ ID NO:102 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO:102.

[0040] In some embodiments, an isolated anti-FXIIa antibody is provided, comprising: (i) V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 7, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 18, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 31; and V L , the V L It comprises: LC-CDR1, which comprises the amino acid sequence of SEQ ID NO:45, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:55, and LC-CDR3, which comprises the amino acid sequence of SEQ ID NO:69.

[0041] In some embodiments, any one of the isolated anti-FXIIa antibodies described above comprises: V H , comprising the amino acid sequence shown in SEQ ID NO: 86 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO: 86; and V L , which comprises the amino acid sequence shown in SEQ ID NO:103 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO:103.

[0042] In some embodiments, an isolated anti-FXIIa antibody is provided, comprising: (i) V H , the V Hcomprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 8, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 19, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 28; and V L , the V L It comprises: LC-CDR1, which comprises the amino acid sequence of SEQ ID NO:46, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:50, and LC-CDR3, which comprises the amino acid sequence of SEQ ID NO:70.

[0043] In some embodiments, any one of the isolated anti-FXIIa antibodies described above comprises: V H , comprising the amino acid sequence shown in SEQ ID NO: 87 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO: 87; and V L , which comprises the amino acid sequence shown in SEQ ID NO:104 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO:104.

[0044] In some embodiments, an isolated anti-FXIIa antibody is provided, comprising: (i) V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 9, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 20, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 32; and V L , the V L It comprises: LC-CDR1, which comprises the amino acid sequence of SEQ ID NO:47, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:51, and LC-CDR3, which comprises the amino acid sequence of SEQ ID NO:71.

[0045] In some embodiments, any one of the isolated anti-FXIIa antibodies described above comprises: V H , comprising the amino acid sequence shown in SEQ ID NO: 88 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO: 88; and V L , which comprises the amino acid sequence shown in SEQ ID NO:105 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO:105.

[0046] In some embodiments, an isolated anti-FXIIa antibody is provided, comprising: (i) V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 3, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 21, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 33; and V L , the V L It comprises: LC-CDR1, which comprises the amino acid sequence of SEQ ID NO:37, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:51, and LC-CDR3, which comprises the amino acid sequence of SEQ ID NO:72.

[0047] In some embodiments, any one of the isolated anti-FXIIa antibodies described above comprises: V H , comprising the amino acid sequence shown in SEQ ID NO: 89 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO: 89; and V L , which comprises the amino acid sequence shown in SEQ ID NO:106 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO:106.

[0048] In some embodiments, the isolated anti-FXIIa antibody binds to human FXIIa with a Kd value of 0.1 pM to 1 nM.

[0049] In some embodiments, any of the anti-FXIIa antibodies isolated as described above, the anti-FXIIa antibody isolated comprises an Fc fragment. In some embodiments, the anti-FXIIa antibody isolated is a full-length IgG antibody. In some embodiments, the anti-FXIIa antibody isolated is a full-length IgG1, IgG2, IgG3 or IgG4 antibody. In some embodiments, the anti-FXIIa antibody isolated is a chimeric, fully human or humanized antibody. In some embodiments, the anti-FXIIa antibody isolated is an antigen-binding fragment selected from Fab, Fab', F(ab)'2, Fab'-SH, single-chain Fv (scFv), Fv fragment, dAb, Fd, nanobody, double-chain antibody (diabody) and linear antibody.

[0050] In some embodiments, an isolated nucleic acid molecule is provided, the nucleic acid molecule encoding any of the anti-FXIIa antibodies described above. In some embodiments, a vector is provided, the vector comprising any of the nucleic acid molecules described above. In some embodiments, a host cell is provided, the host cell comprising any of the anti-FXIIa antibodies described above, any of the nucleic acid molecules described above, or any of the vectors described above. In some embodiments, a method for preparing an anti-FXIIa antibody is provided, comprising: a) culturing any of the host cells described above under conditions that effectively express the anti-FXIIa antibody; and b) obtaining the expressed anti-FXIIa antibody from the host cell.

[0051] In some embodiments, a method for treating a desired individual disease or condition is provided, comprising administering to the individual an effective amount of any anti-FXIIa antibody as described above. In some embodiments, the use of any anti-FXIIa antibody as described above in the preparation of a pharmaceutical composition for treating a desired individual disease or condition is provided. In some embodiments, the use of any anti-FXIIa antibody as described above or a pharmaceutical composition comprising an anti-FXIIa antibody in the preparation of a medicament for treating a disease or condition is provided. In some embodiments, the disease or condition is associated with the FXIIa signaling pathway, including thrombosis, diseases associated with FXII / FXIIa-induced kinin formation, diseases associated with FXII / FXIIa-induced complement activation, diseases associated with the contact activation system, and inflammation-related diseases or conditions. In some embodiments, the disease or disorder is selected from, for example, venous, arterial or capillary thrombosis, intracardiac thrombosis, thrombosis during and / or after contacting the blood of a human or animal subject with an artificial surface, thromboembolism, atherosclerosis, interstitial lung disease, inflammation, neuroinflammatory diseases, neurotraumatic diseases, traumatic brain injury, complement activation, fibrinolysis, angiogenesis, hereditary angioedema (HAE), bacterial infection of the lung, Trypanosoma infection, hypotensive shock, pancreatitis, chagas disease, arthritis, arthritis, disseminated intravascular coagulation and sepsis, macular edema, diabetic retinopathy, hypertensive retinopathy, age-related macular degeneration, retinal vein occlusion, organ ischemia, distal ischemia-reperfusion injury (IRI), chronic kidney disease, renal fibrosis, multiple sclerosis.

[0052] Also provided are pharmaceutical compositions, kits, and manufactured articles comprising any of the anti-FXIIa antibodies described above. BRIEF DESCRIPTION OF THE DRAWINGS

[0053] Figure 1Shown are the results of the inhibition of FXIIa cleavage of PK proenzyme by exemplary anti-FXIIa antibodies FX-M37, FX-M40, and FX-M43 using the pKa chemical substrate CS-3102.

[0054] Figure 2 Shown are the results of the inhibitory effects of exemplary anti-FXIIa antibodies FX-M37, FX-M40, and FX-M43 on FXIIa-induced coagulation using APTT assay.

[0055] Figure 3 Shown are the results of the inhibitory effects of exemplary anti-FXIIa antibodies FX-KO49, FX-KO50, FX-KO51, FX-KO56, FX-KO71, FX-KO72, and FX-KO74 on FXIIa-induced coagulation using APTT assay.

[0056] Detailed description of this application

[0057] The present application provides an anti-FXIIa antibody molecule on the one hand. Through a combination of natural scFv phage library screening and appropriately designed biochemical and biological experiments, an efficient antibody molecule capable of binding to human FXIIa and inhibiting the interaction of human FXIIa with its receptor has been identified. The results given herein show that compared with the known anti-FXIIa antibody CSL312 (CSL), the antibody in the present application binds to different regions or epitopes of FXIIa, and surprisingly, the antibody in the present application has been shown to be even more effective than CSL312 in various biological experiments.

[0058] The anti-FXIIa antibodies provided herein include, for example, full-length anti-FXIIa antibodies, anti-FXIIa single-chain antibodies (scFvs), anti-FXIIa Fc fusion proteins, multispecific (eg, bispecific) anti-FXIIa antibodies, anti-FXIIa immunoconjugates, and the like.

[0059] On the other hand, the present application provides an anti-FXIIa antibody, wherein the anti-FXIIa antibody comprises: a heavy chain variable domain (V H ), the V H The invention comprises: a heavy chain complementary determining region (HC-CDR) 1 comprising SYVMH (SEQ ID NO: 1); HC-CDR2 comprising YINPYNDVTKYNEKFKG (SEQ ID NO: 10); and HC-CDR3 comprising ARTYSLDY (SEQ ID NO: 22); and a light chain variable domain (V L ), the V LIt comprises: a light chain complementary determining region (LC-CDR) 1 comprising KASQNVGTNVA (SEQ ID NO: 34); a LC-CDR2 comprising SASYRYS (SEQ ID NO: 48); and a LC-CDR3 comprising QQYNSYPRT (SEQ ID NO: 56).

[0060] On the other hand, the present application provides an anti-FXIIa antibody, wherein the anti-FXIIa antibody comprises: a heavy chain variable domain (V H ), the V H The invention comprises: a heavy chain complementary determining region (HC-CDR) 1 comprising SYVMH (SEQ ID NO: 1); HC-CDR2 comprising YINPFNGVTKYNEKFKD (SEQ ID NO: 11); and HC-CDR3 comprising ARTYALDY (SEQ ID NO: 23); and a light chain variable domain (V L ), the V L It comprises: a light chain complementary determining region (LC-CDR) 1 comprising KATQNVGTNVA (SEQ ID NO: 35); a LC-CDR2 comprising SASYRNS (SEQ ID NO: 49); and a LC-CDR3 comprising QQYNIYPRT (SEQ ID NO: 57).

[0061] On the other hand, the present application provides an anti-FXIIa antibody, wherein the anti-FXIIa antibody comprises: a heavy chain variable domain (V H ), the V H The heavy chain complementary determining region (HC-CDR) 1 comprises SYGMS (SEQ ID NO: 2); HC-CDR2 comprises AINNNGGITYYPDSVKG (SEQ ID NO: 12); and HC-CDR3 comprises GRGITDY (SEQ ID NO: 24); and a light chain variable domain (V L ), the V L It comprises: a light chain complementary determining region (LC-CDR) 1 comprising SARSSVSYMY (SEQ ID NO: 36); a LC-CDR2 comprising DTSNLAS (SEQ ID NO: 50); and a LC-CDR3 comprising QQWSSNPYT (SEQ ID NO: 58).

[0062] On the other hand, the present application provides an anti-FXIIa antibody, wherein the anti-FXIIa antibody comprises: a heavy chain variable domain (V H ), the V HThe invention comprises: a heavy chain complementary determining region (HC-CDR) 1 comprising TYTMH (SEQ ID NO: 3); HC-CDR2 comprising YFNPSSGYSNYNQKFKD (SEQ ID NO: 13); and HC-CDR3 comprising FPFAY (SEQ ID NO: 25); and a light chain variable domain (V L ), the V L It comprises: a light chain complementary determining region (LC-CDR) 1 comprising SASSVSYMH (SEQ ID NO: 37); a LC-CDR2 comprising DTSKLAS (SEQ ID NO: 51); and a LC-CDR3 comprising QQWSSNPLT (SEQ ID NO: 59).

[0063] On the other hand, the present application provides an anti-FXIIa antibody, wherein the anti-FXIIa antibody comprises: a heavy chain variable domain (V H ), the V H The invention comprises: a heavy chain complementary determining region (HC-CDR) 1 comprising SGYSWH (SEQ ID NO: 4); HC-CDR2 comprising YIQYNGNTNSNPSLKS (SEQ ID NO: 14); and HC-CDR3 comprising WGTMDY (SEQ ID NO: 26); and a light chain variable domain (V L ), the V L It comprises: a light chain complementary determining region (LC-CDR) 1 comprising SASSVSYMH (SEQ ID NO: 37); a LC-CDR2 comprising DTSKLAS (SEQ ID NO: 51); and a LC-CDR3 comprising QQWSSNPPT (SEQ ID NO: 60).

[0064] On the other hand, the present application provides an anti-FXIIa antibody, wherein the anti-FXIIa antibody comprises: a heavy chain variable domain (V H ), the V H The invention comprises: a heavy chain complementary determining region (HC-CDR) 1 comprising TYTMH (SEQ ID NO: 3); HC-CDR2 comprising YFNPSSGYSNYNQKFKD (SEQ ID NO: 13); and HC-CDR3 comprising FPFAY (SEQ ID NO: 25); and a light chain variable domain (V L ), the V LIt comprises: a light chain complementary determining region (LC-CDR) 1 comprising SASSVSYMH (SEQ ID NO: 37); a LC-CDR2 comprising DTSKLAS (SEQ ID NO: 51); and a LC-CDR3 comprising QQYSGFPLT (SEQ ID NO: 61).

[0065] On the other hand, the present application provides an anti-FXIIa antibody, wherein the anti-FXIIa antibody comprises: a heavy chain variable domain (V H ), the V H The heavy chain complementary determining region (HC-CDR) 1 comprises SYGMS (SEQ ID NO: 2); HC-CDR2 comprises AINNNGGITYYPDSVKG (SEQ ID NO: 12); and HC-CDR3 comprises GRGITDY (SEQ ID NO: 24); and a light chain variable domain (V L ), the V L It comprises: a light chain complementary determining region (LC-CDR) 1 comprising SASSVSYMY (SEQ ID NO: 38); a LC-CDR2 comprising DTSNLAS (SEQ ID NO: 50); and a LC-CDR3 comprising QQWSSYPYT (SEQ ID NO: 62).

[0066] On the other hand, the present application provides an anti-FXIIa antibody, wherein the anti-FXIIa antibody comprises: a heavy chain variable domain (V H ), the V H The invention comprises: a heavy chain complementary determining region (HC-CDR) 1 comprising TYTMH (SEQ ID NO: 3); HC-CDR2 comprising YFNPSSGYSNYNQKFKD (SEQ ID NO: 13); and HC-CDR3 comprising FPFAY (SEQ ID NO: 25); and a light chain variable domain (V L ), the V L It comprises: a light chain complementary determining region (LC-CDR) 1 comprising SASSSVTYMH (SEQ ID NO: 39); a LC-CDR2 comprising DTSRLAS (SEQ ID NO: 52); and a LC-CDR3 comprising QQWSSNPST (SEQ ID NO: 63).

[0067] On the other hand, the present application provides an anti-FXIIa antibody, wherein the anti-FXIIa antibody comprises: a heavy chain variable domain (V H ), the V HThe invention comprises: a heavy chain complementary determining region (HC-CDR) 1 comprising SYVMH (SEQ ID NO: 1); HC-CDR2 comprising YINPYNDVTKYNEKFKG (SEQ ID NO: 10); and HC-CDR3 comprising PYPSYTMDS (SEQ ID NO: 27); and a light chain variable domain (V L ), the V L It comprises: a light chain complementary determining region (LC-CDR) 1 comprising RASQNVGTNVA (SEQ ID NO: 40); a LC-CDR2 comprising STSYRYS (SEQ ID NO: 53); and a LC-CDR3 comprising QQYYTYPYT (SEQ ID NO: 64).

[0068] On the other hand, the present application provides an anti-FXIIa antibody, wherein the anti-FXIIa antibody comprises: a heavy chain variable domain (V H ), the V H The invention comprises: a heavy chain complementary determining region (HC-CDR) 1 comprising NYRMH (SEQ ID NO: 5); HC-CDR2 comprising YINPSSGYTKNIQKFKD (SEQ ID NO: 15); and HC-CDR3 comprising NPFSY (SEQ ID NO: 28); and a light chain variable domain (V L ), the V L It comprises: a light chain complementary determining region (LC-CDR) 1 comprising SANSSVNYIH (SEQ ID NO: 41); a LC-CDR2 comprising DTSNLAS (SEQ ID NO: 50); and a LC-CDR3 comprising QQWSSYPFT (SEQ ID NO: 65).

[0069] On the other hand, the present application provides an anti-FXIIa antibody, wherein the anti-FXIIa antibody comprises: a heavy chain variable domain (V H ), the V H The invention comprises: a heavy chain complementary determining region (HC-CDR) 1 comprising SYTMH (SEQ ID NO: 6); HC-CDR2 comprising YINPSSGFTKYNQKFKD (SEQ ID NO: 16); and HC-CDR3 comprising YPFYYDYGY (SEQ ID NO: 29); and a light chain variable domain (V L ), the V LIt comprises: a light chain complementary determining region (LC-CDR) 1 comprising SANSSVTYMY (SEQ ID NO: 42); a LC-CDR2 comprising DTSILTS (SEQ ID NO: 54); and a LC-CDR3 comprising QQWSSYPIT (SEQ ID NO: 66).

[0070] On the other hand, the present application provides an anti-FXIIa antibody, wherein the anti-FXIIa antibody comprises: a heavy chain variable domain (V H ), the V H The invention comprises: a heavy chain complementary determining region (HC-CDR) 1 comprising SYTMH (SEQ ID NO: 6); HC-CDR2 comprising YSNPSSGYTKYNQKFKD (SEQ ID NO: 17); and HC-CDR3 comprising YPFYYDSGY (SEQ ID NO: 30); and a light chain variable domain (V L ), the V L It comprises: a light chain complementary determining region (LC-CDR) 1 comprising SASSSVNYMY (SEQ ID NO: 43); a LC-CDR2 comprising DTSNLAS (SEQ ID NO: 50); and a LC-CDR3 comprising QQWSSYPLT (SEQ ID NO: 67).

[0071] On the other hand, the present application provides an anti-FXIIa antibody, wherein the anti-FXIIa antibody comprises: a heavy chain variable domain (V H ), the V H The invention comprises: a heavy chain complementary determining region (HC-CDR) 1 comprising NYRMH (SEQ ID NO: 5); HC-CDR2 comprising YINPSSGYTKNIQKFKD (SEQ ID NO: 15); and HC-CDR3 comprising NPFSY (SEQ ID NO: 28); and a light chain variable domain (V L ), the V L It comprises: a light chain complementary determining region (LC-CDR) 1 comprising SASSSINYIH (SEQ ID NO: 44); a LC-CDR2 comprising DTSNLAS (SEQ ID NO: 50); and a LC-CDR3 comprising QQWSSSPFT (SEQ ID NO: 68).

[0072] On the other hand, the present application provides an anti-FXIIa antibody, wherein the anti-FXIIa antibody comprises: a heavy chain variable domain (V H ), the V HThe invention comprises: a heavy chain complementary determining region (HC-CDR) 1 comprising DYYMN (SEQ ID NO: 7); HC-CDR2 comprising DINPYNGGTSYNQKFKG (SEQ ID NO: 18); and HC-CDR3 comprising FTTVVEGYAMDY (SEQ ID NO: 31); and a light chain variable domain (V L ), the V L It comprises: a light chain complementary determining region (LC-CDR) 1 comprising KASQNVGSNVA (SEQ ID NO: 45); a LC-CDR2 comprising SASHRYS (SEQ ID NO: 55); and a LC-CDR3 comprising QQYNSYPLT (SEQ ID NO: 69).

[0073] On the other hand, the present application provides an anti-FXIIa antibody, wherein the anti-FXIIa antibody comprises: a heavy chain variable domain (V H ), the V H The invention comprises: a heavy chain complementary determining region (HC-CDR) 1 comprising NYRIH (SEQ ID NO: 8); HC-CDR2 comprising YINPSSGYTKYIQKFKD (SEQ ID NO: 19); and HC-CDR3 comprising NPFSY (SEQ ID NO: 28); and a light chain variable domain (V L ), the V L It comprises: a light chain complementary determining region (LC-CDR) 1 comprising SANSSLTYIH (SEQ ID NO: 46); a LC-CDR2 comprising DTSNLAS (SEQ ID NO: 50); and a LC-CDR3 comprising QQWSTFPFT (SEQ ID NO: 70).

[0074] On the other hand, the present application provides an anti-FXIIa antibody, wherein the anti-FXIIa antibody comprises: a heavy chain variable domain (V H ), the V H The invention comprises: a heavy chain complementary determining region (HC-CDR) 1 comprising NYWMH (SEQ ID NO: 9); HC-CDR2 comprising MIHPNFGRTKENEKFKS (SEQ ID NO: 20); and HC-CDR3 comprising SPFPI (SEQ ID NO: 32); and a light chain variable domain (V L ), the V LIt comprises: a light chain complementary determining region (LC-CDR) 1 comprising SASSGVNYVH (SEQ ID NO: 47); a LC-CDR2 comprising DTSKLAS (SEQ ID NO: 51); and a LC-CDR3 comprising QQWYDYPLT (SEQ ID NO: 71).

[0075] On the other hand, the present application provides an anti-FXIIa antibody, wherein the anti-FXIIa antibody comprises: a heavy chain variable domain (V H ), the V H The invention comprises: a heavy chain complementary determining region (HC-CDR) 1 comprising TYTMH (SEQ ID NO: 3); HC-CDR2 comprising YINPSSGYIKYNQRFKD (SEQ ID NO: 21); and HC-CDR3 comprising YPYAPGFDV (SEQ ID NO: 33); and a light chain variable domain (V L ), the V L It comprises: a light chain complementary determining region (LC-CDR) 1 comprising SASSVSYMH (SEQ ID NO: 37); a LC-CDR2 comprising DTSKLAS (SEQ ID NO: 51); and a LC-CDR3 comprising QQYSGYPLT (SEQ ID NO: 72).

[0076] Also provided are nucleic acids encoding anti-FXIIa antibodies, compositions comprising anti-FXIIa antibodies, and methods of making and using anti-FXIIa antibodies.

[0077] definition

[0078] As used herein, "treatment" or "treating" is a method of obtaining beneficial or desired results, including clinical results. For the purposes of this application, the beneficial or desired clinical results include, but are not limited to, one or more of the following: alleviating one or more symptoms caused by the disease, alleviating the extent of the disease, stabilizing the disease (e.g., preventing or delaying disease progression), preventing or delaying the spread of the disease (e.g., metastasis), preventing or delaying disease recurrence, delaying or slowing disease progression, improving the disease state, alleviating the disease (partially or completely), reducing the dose of one or more other drugs required to treat the disease, delaying disease progression, improving or enhancing the quality of life, inhibiting coagulation, and / or inhibiting thrombosis. At the same time, "treatment" also includes a reduction in the pathological consequences of the disease (e.g., vascular permeability for hereditary angioedema). The methods of the present application take into account any one or more aspects of these treatments.

[0079] The term "antibody" includes full-length antibodies and antigen-binding fragments thereof. Full-length antibodies include two heavy chains and two light chains. The variable regions of the light and heavy chains are responsible for antigen binding. The variable regions in the two chains usually include three hypervariable loops, known as complementarity determining regions (CDRs) (light chain (LC) CDRs include LC-CDR1, LC-CDR2 and LC-CDR3, and heavy chain (HC) CDRs include HC-CDR1, HC-CDR2 and HC-CDR3). The CDR boundaries of the antibodies or antigen-binding fragments disclosed herein can be defined or identified by the Kabat, Chothia or Al-Lazikani conventions (Al-Lazikani 1997; Chothia 1985; Chothia 1987; Chothia 1989; Kabat 1987; Kabat 1991). The three CDR regions of the heavy or light chain are inserted between flanking segments called framework regions (FRs), which are more highly conserved than the CDR regions and form a scaffold that supports the hypervariable loops. The constant regions of the heavy and light chains are not involved in antigen binding, but exhibit a variety of effector functions. Antibodies are classified based on the amino acid sequence of their heavy chain constant regions. The five major classes or isotypes of antibodies are IgA, IgD, IgE, IgG, and IgM, characterized by having α, δ, ε, γ, and μ heavy chains, respectively. Several major antibody classes are divided into subclasses, such as IgG1 (γ1 heavy chain), IgG2 (γ2 heavy chain), IgG3 (γ3 heavy chain), IgG4 (γ4 heavy chain), IgA1 (α1 heavy chain), or IgA2 (α2 heavy chain).

[0080] As described herein, the term "antigen-binding fragment" includes antibody fragments, such as diabodies, Fab, Fab', F(ab')2, Fv fragments, disulfide-stabilized Fv fragments (dsFv), (dsFv)2, bispecific dsFv (dsFv-dsFv'), disulfide-stabilized diabodies (dsdiabodies), single-chain Fv (scFv), scFv dimers (divalent diabodies), multispecific antibodies composed of antibody fragments comprising one or more CDRs, single-domain antibodies, nanobodies, domain antibodies, divalent domain antibodies, or any other antibody fragment that can bind to an antigen but does not contain a complete antibody structure. Antigen-binding fragments can bind to the same antigen as a parent antibody or a parent antibody fragment (such as a parent scFv). Antigen-binding fragments also include fusion proteins comprising the above-mentioned antibody fragments. In some embodiments, an antigen-binding fragment may include one or more CDRs from a specific human antibody, which are transplanted to the framework region from one or more different human antibodies.

[0081] As used herein, the term "epitope" refers to a specific group of atoms or amino acids on an antigen to which an antibody or antibody portion binds. If two antibodies or antibody portions exhibit competitive binding to an antigen, they are likely to bind to the same epitope on the antigen.

[0082] As used herein, a first antibody "competes" for binding to a second antibody for a FXIIa target when the first antibody inhibits binding of the second antibody to the FXIIa target by at least 50% (e.g., at least 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99%) at equimolar concentrations, and vice versa. PCT Publication WO 03 / 48731 describes a high throughput antibody "epitope binning" method based on cross-competition.

[0083] As used herein, the terms "specifically bind", "specifically recognize" or "specific for" refer to a measurable and reproducible interaction, such as the binding of an antibody to a target that can determine the presence of the target in a heterogeneous population of molecules, including biomolecules. For example, an antibody can specifically recognize a target (which can be an epitope) means that the antibody binds to the target with higher affinity, avidity, more readily and / or more persistently than other targets. In some embodiments, an antibody that specifically recognizes an antigen reacts with one or more antigenic determinants of the antigen with an affinity that is at least 10 times greater than its binding affinity to other targets.

[0084] As used herein, an "isolated" anti-FXIIa antibody refers to an anti-FXIIa antibody that (1) is not related to naturally occurring proteins, (2) does not contain other proteins from the same source, (3) is expressed by cells of a different species, or (4) does not exist in nature.

[0085] As used herein, the term "isolated nucleic acid" refers to nucleic acids of genomic, cDNA or synthetic origin or a combination thereof. Depending on its source, the "isolated nucleic acid" refers to (1) all or part of the polynucleotides in the "isolated nucleic acid" found in nature,

[0086] (2) can be operably linked to a polynucleotide with which it is not naturally associated, or (3) does not occur in nature as part of a longer sequence.

[0087] As used herein, the term "CDR" or "complementarity determining region" refers to the non-contiguous antigen binding sites found within the variable domains of heavy and light chain polypeptides. In the literature Kabatet al., J. Biol. Chem. 252: 6609-6616 (1977); Kabat et al., USDept. of Health and Human Services, "Sequences of proteins of immunological interest" (1991); Chothia et al., J. Mol. Biol. 196: 901-917 (1987); Al-Lazikani B. et al. al., J. Mol. Biol., 273: 927-948 (1997); MacCallum et al., J. Mol. Biol. 262: 732-745 (1996); Abhinandan and Martin, Mol. Immunol., 45: 3832-3839 (2008); Lefranc MPet al., Dev. Comp. Immunol., 27: 55-77 (2003); and Honegger and Plückthun, J. Mol. Biol., 309: 657-670 (2001), wherein these definitions include overlaps or subsets of amino acid residues when compared to each other. However, any definition used to indicate the CDR of an antibody or transplanted antibody or a variant thereof is included in the terms defined and used herein. Table 1 lists the positions of the amino acid residues included in the CDRs defined by the references cited above for comparison. Algorithms and binding interfaces for CDR prediction are known in the art, including, for example, Abhinandan and Martin, Mol. Immunol., 45: 3832-3839 (2008);

[0088] Ehrenmann F. et al., Nucleic Acids Res., 38: D301-D307 (2010); and Adolf-Bryfogle J. et al., Nucleic Acids Res., 43: D432-D438 (2015). The contents of the references cited in this paragraph are incorporated herein by reference in their entirety for use in this application and in one or more claims that may be included in this article.

[0089] Table 1: CDR definitions

[0090]

[0091]

[0092] 1 The amino acid residue numbers refer to the nomenclature of Kabat et al.

[0093] 2 The amino acid residue numbers refer to the nomenclature of Chothia et al.

[0094] 3 The amino acid residue numbers refer to the nomenclature of MacCallum et al.

[0095] 4 The amino acid residue numbers refer to the nomenclature of Lefranc et al.

[0096] 5 The amino acid residue numbers refer to the nomenclature of Honegger and Plückthun above.

[0097] The term "chimeric antibody" refers to an antibody in which a portion of the heavy chain and / or light chain is identical or homologous to a corresponding sequence in an antibody from a particular species or belonging to a particular antibody class or subclass, and the remainder of the chain(s) is identical or homologous to a corresponding sequence in an antibody from another genus or belonging to another antibody class or subclass, as well as fragments of such antibodies, as long as they have the biological activity described in the present application (see US Patent No. 4,816,567; and Morrison et al., Proc. Natl. Acad. Sci. USA, 81: 6851-6855 (1984)).

[0098] "Fv" is the smallest antibody fragment that contains a complete antigen recognition and binding site. This fragment is a dimer formed by a heavy chain variable domain and a light chain variable domain tightly non-covalently linked. Six hypervariable loops (3 loops each in the light chain and heavy chain) are derived from the folding of these two domains, which provide the antibody with amino acid residues for binding to the antigen and give the antibody specificity for binding to the antigen. However, even a single variable domain (or half of an Fv fragment, which contains only 3 CDRs specific for the antigen) has the ability to recognize and bind to the antigen, although its affinity is lower than that of the complete binding site.

[0099] "Single-chain Fv", also abbreviated as "sFv" or "scFv", is a Fv comprising V linked into a single polypeptide chain. H and V L In some embodiments, the scFv polypeptide further comprises a VH and V L The connecting polypeptide between the domains allows the scFv to form an ideal structure for antigen binding. For an overview of scFv, see Pluckthun in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., Springer-Verlag, New York, pp. 269-315 (1994).

[0100] The term "diabody" is used in V H and V L A small antibody fragment prepared by constructing scFv fragments (see above) with short linkers (e.g., 5 to 10 residues) between the domains, so that the variable domains pair between chains rather than within the chains, producing a bivalent fragment, that is, a fragment with two antigen-binding sites. A bispecific diabody is a heterodimer of two "crossed" scFv fragments, in which the V H and V L The domains are located on different polypeptide chains. Diabodies are fully described in EP 404,097; WO 93 / 11161; Hollinger et al., Proc. Natl. Acad. Sci. USA, 90:6444-6448 (1993).

[0101] The "humanized" form of a non-human (such as rodent) antibody is a chimeric antibody that includes minimal sequences from a non-human antibody. In most cases, a humanized antibody is a human immunoglobulin (receptor antibody) in which the hypervariable region (HVR) residues of the receptor antibody are replaced by residues from a non-human species such as a mouse, rat, rabbit or non-human mammal with an ideal antibody specificity, affinity and performance (donor antibody). In some cases, residues in the framework region of a human immunoglobulin are replaced by corresponding non-human residues. In addition, a humanized antibody may include residues that are not present in either the receptor antibody or the donor antibody. These modifications can further improve the performance of the antibody. Typically, a humanized antibody will include substantially all, at least one, and usually two variable domains, wherein all or substantially all of the hypervariable loops correspond to the hypervariable loops of a non-human immunoglobulin, and all or substantially all of the framework regions are human immunoglobulin sequences. Human antibodies optionally also include at least a portion of an immunoglobulin constant region (Fc), typically a constant region of a human immunoglobulin. For details, see Jones et al., Nature 321: 522-525 (1986); Riechmann et al., Nature 332: 323-329 (1988); and Presta, Curr. Op. Struct. Biol. 2: 593-596 (1992).

[0102] The "percent (%) amino acid sequence identity" or "homology" of the polypeptide and antibody sequences identified herein is defined as the percentage of identical amino acid residues in a candidate sequence and the polypeptide sequence to be compared, when conservative substitutions are considered to be part of the sequence identity. The percentage of amino acid sequence identity can be determined by a variety of alignment methods within the skill of the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN, Megalign (DNASTAR), or MUSCLE software. One skilled in the art can determine appropriate parameters for measuring alignment, including any algorithm required to maximize alignment over the entire length of the compared sequences. However, for the purposes of this article, the percentage of amino acid sequence identity values ​​are generated using the sequence alignment computer program MUSCLE (Edgar, RC, Nucleic Acids Research 32 (5): 1792-1797, 2004; Edgar, RC, BMC Bioinformatics 5 (1): 113, 2004).

[0103] The term "Fc receptor" or "FcR" is used to describe a receptor that binds to the Fc region of an antibody. In some embodiments, the FcR described herein is an FcR that binds to an IgG antibody (a gamma receptor), including receptors of the FcγRI, FcγRII, and FcγRIII subclasses, including allelic variants and alternative splicing forms of these receptors. FcγRII receptors include FcγRIIA ("activating receptor") and FcγRIIB ("inhibiting receptor"), which have similar amino acid sequences and differ primarily in the cytoplasmic domain. The cytoplasmic domain of the activating receptor FcγRIIA contains an immunoreceptor tyrosine-based activation motif (ITAM). The cytoplasmic domain of the inhibitory receptor FcγRIIB contains an immunoreceptor tyrosine-based inhibition motif (ITIM) (see M.in Annu. Rev. Immunol. 15: 203-234 (1997)). The term also includes allotypes, such as the FcγRIIIA allotypes: FcγRIIIA-Phe158, FcγRIIIA-Val158, FcγRIIA-R131 and / or FcγRIIA-H131. FcRs are described in Ravetch and Kinet, Annu. Rev. Immunol 9: 457-92 (1991) and Capel et al., Immunomethods 4: 25-34 (1994); and de Haas et al., J. Lab. Clin. Med. 126: 330-41 (1995). The term FcR in this application encompasses other types of FcRs, including those identified in the future. The term FcR also includes the neonatal receptor FcRn, which is responsible for the transfer of maternal IgGs to the newborn (Guyer et al., J. Immunol. 117:587 (1976) and Kim et al., J. Immunol. 24:249 (1994)).

[0104] The term "FcRn" refers to the neonatal Fc receptor (FcRn). FcRn is structurally similar to the major histocompatibility complex (MHC) and consists of an α chain non-covalently bound to β2 microglobulin. The various functions of the neonatal Fc receptor FcRn are reviewed in Ghetie and Ward (2000) Annu. Rev. Immunol. 18, 739-766. FcRn plays an important role in the passive transport of immunoglobulins IgGs from mothers to newborns and in regulating serum IgG levels. As a rescue receptor, FcRn can bind and transport endocytosed IgG in an intact form within and between cells, and protect them from the default degradation pathway.

[0105] The "CH1 domain" of a human IgG heavy chain constant region typically stretches from amino acid 118 to amino acid 215 (EU numbering system).

[0106] The "hinge region" is generally defined as extending from Glu 216 to Pro 230 of human IgG1 (Burton, Molec. Immunol. 22: 161-206 (1985)). By placing the first and last cysteine ​​residues that form inter-heavy chain disulfide bonds in the same position as IgG1, the hinge regions of other IgG isotypes can be aligned with the IgG1 sequence.

[0107] The "CH2 domain" of the human IgG Fc region usually extends from amino acid 231 to amino acid 340. The uniqueness of the CH2 domain is that it does not pair closely with another region, but rather two N-terminally connected branched sugar chains are inserted between the two CH2 domains of the intact native IgG molecule. It is speculated that carbohydrates may serve as a substitute for domain-to-domain pairing, helping to maintain the stability of the CH2 domain. Burton, Molec. Immunol. 22: 161-206 (1985).

[0108] The "CH3" domain includes the stretch from the C-terminal residue to the CH2 domain within the Fc region (from amino acid 341 to the C-terminus of the antibody sequence, generally amino acid residue 446 or 447 for IgG).

[0109] A "functional Fc fragment" has the "effector functions" possessed by a native Fc region sequence. Exemplary "effector functions" include C1q binding; complement-dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; downregulation of cell surface receptors (such as B cell receptor; BCR), etc. Such effector functions generally require the Fc region to be combined with a binding domain (such as an antibody variable region) and can be evaluated using a variety of experimental methods known in the art.

[0110] An antibody having an IgG Fc variant with "altered" FcR binding affinity or ADCC activity has increased or decreased FcR binding activity and / or ADCC activity compared to the parent polypeptide or a polypeptide comprising a native Fc sequence. An Fc variant exhibiting "enhanced binding" to an FcR has a higher binding affinity (e.g., lower apparent Kd or ICd) to at least one FcR compared to the parent polypeptide or a polypeptide comprising a native IgG Fc sequence. 50In some embodiments, the binding capacity is enhanced by 3-fold, such as 5, 10, 25, 50, 60, 100, 150, 200, or even up to 500-fold, or the binding capacity is increased by 25% to 1000% compared to the parent polypeptide. An Fc variant that exhibits "reduced binding" to an FcR has a lower affinity (e.g., a higher apparent Kd or ICd) for at least one FcR compared to the parent polypeptide. 50 Compared with the parent polypeptide, its binding capacity is reduced by 40% or more.

[0111] "Antibody-dependent cell-mediated cytotoxicity" or "ADCC" is a form of cytotoxicity that refers to the binding of secreted Ig to Fc receptors (FcRs) present on certain cytotoxic cells (e.g., natural killer (NK) cells, neutrophils, and macrophages), enabling these cytotoxic effector cells to specifically bind to target cells bearing antigens and subsequently kill the target cells using cytotoxins. Antibodies "arm" the cytotoxic cells and are required for this killing. Of the major cell types that mediate ADCC, NK cells express only FcγRIII, while monocytes express FcγRI, FcγRII, and FcγRIII. The expression of FcRs on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet, Annu. Rev. Immunol 9:457-92 (1991). To assess the ADCC activity of a target molecule, an in vitro ADCC assay can be performed, as described in U.S. Pat. Nos. 5,500,362 or 5,821,337. Effector cells suitable for such experiments include peripheral blood mononuclear cells (PBMC) and natural killer cells (NK). Alternatively, or in addition, ADCC activity of the target molecule can also be assessed in vivo, for example, as described in an animal model disclosed in Clynes et al. PNAS (USA) 95: 652-656 (1998).

[0112] The polypeptide comprising the Fc region variant exhibits "enhanced ADCC activity" or can more effectively mediate the ADCC effect in the presence of human effector cells compared to the polypeptide comprising the wild-type IgG Fc polypeptide or the parent polypeptide. The polypeptide comprising the Fc region variant can more effectively mediate ADCC in vitro or in vivo when the number of polypeptides comprising the wild-type IgG Fc polypeptide (or the parent polypeptide) is substantially the same during the experiment. Such variants are generally identified using any in vitro ADCC experimental method known in the art, such as an experiment or method for identifying ADCC activity, such as in an animal model, etc. In some embodiments, such variants mediate ADCC with an efficiency of 5 to 100 times, such as 25 to 50 times, compared to the wild-type Fc (or the parent polypeptide).

[0113] "Complement-dependent cytotoxicity" or "CDC" refers to the lysis of target cells in the presence of complement. Activation of the classical complement pathway is initiated by the binding of the first component of the complement system (C1q) to an antibody (of the appropriate structural subclass) that binds to a cognate antigen. To assess complement activation, a CDC assay may be performed, such as that described in Gazzano-Santoro et al., J. Immunol. Methods 202: 163 (1996). Polypeptide variants having altered Fc region amino acid sequences and increased or decreased C1q binding ability are described in U.S. Patent No. 6,194,551 B1 and WO 99 / 51642. The contents of these patent publications are expressly incorporated herein by reference. See also Idusogie et al. J. Immunol. 164: 4178-4184 (2000).

[0114] Unless otherwise specified, a "nucleotide sequence encoding an amino acid sequence" includes all nucleotide sequences that are degenerate forms of each other and encode the same amino acid sequence. A nucleotide sequence encoding a protein or RNA may also include introns, for example, a nucleotide sequence encoding a protein contains introns in some forms.

[0115] The term "operably linked" refers to a functional connection between a regulatory sequence and a heterologous nucleotide sequence, thereby allowing the latter to be expressed. For example, a first nucleotide sequence is operably linked to a second nucleotide sequence when the first nucleotide sequence is in a functional relationship with the second nucleotide sequence. For example, if a promoter affects the transcription or expression of a coding sequence, the promoter is operably linked to a coding sequence. Generally, operably linked DNA sequences are contiguous and, if necessary, two protein coding regions can be linked in the same reading frame.

[0116] "Homologous" refers to the sequence similarity or sequence identity between two polypeptides or between two nucleic acid molecules. If the same position of two compared sequences is the same base or amino acid monomer subunit, for example, the same position of two DNA molecules is adenine, then the two DNA molecules are homologous at that position. The homology percentage between two sequences refers to the ratio of the number of matching or homologous positions shared by the two sequences to the total number of positions multiplied by 100. For example, if 6 out of 10 positions in two sequences are matched or homologous, the homology of the two sequences is 60%. For example, the DNA sequences ATTGCC and TATGGC have 50% homology. Generally speaking, when aligning two sequences, the comparison is performed with the goal of obtaining maximum homology.

[0117] An "effective amount" of an anti-FXIIa antibody or composition disclosed herein refers to an amount sufficient to achieve a specific purpose. An "effective amount" can be determined empirically and by known methods relevant to the purpose.

[0118] The term "therapeutically effective amount" refers to an amount of the anti-FXIIa antibody or composition thereof disclosed herein that is effective in treating a disease or symptom of an individual. For example, in the case of cancer, a therapeutically effective amount of an anti-FXIIa antibody or composition thereof refers to an amount that can inhibit (i.e., slow down to some extent) FXII / FXIIa enzyme activity; prolong (i.e., prolong to some extent) activated partial thromboplastin time (aPTT); reduce (i.e., eliminate to some extent) the size and / or volume of thrombus formation; reduce (i.e., eliminate to some extent) fibrin deposition; reduce (i.e., eliminate to some extent) platelet deposition; reduce vascular occlusion rate; increase vascular permeability; inhibit (i.e., slow down or preferably stop to some extent) the overactivation of kallikrein; alleviate one or more symptoms associated with thrombosis to some extent. The anti-FXIIa antibody or composition thereof disclosed herein is capable of preventing and / or killing existing tumor cells to some extent, which can be cytostatic or cytotoxic. In some embodiments, a therapeutically effective amount refers to an amount that can prolong the survival of a patient. In some embodiments, a therapeutically effective amount refers to an amount that can improve the progression-free survival of a patient.

[0119] As used herein, "pharmaceutically acceptable" or "pharmacologically compatible" refers to materials that are free of biological activity or other undesirable properties, such as materials that can be added to a pharmaceutical composition administered to a patient without causing significant adverse biological reactions, or that do not interact in a harmful manner with any other components contained in the composition. Pharmaceutically acceptable carriers or excipients preferably meet the required standards for toxicology or manufacturing testing and / or are included in the inactive ingredient guide compiled by the U.S. Food and Drug Administration.

[0120] The embodiments of the present application described herein should be understood to include "consisting of" and / or "consisting essentially of" embodiments.

[0121] Reference herein to "about" for a value or parameter includes (and describes) variations for the value or parameter itself. For example, a description involving "about X" includes a description of "X".

[0122] As used herein, reference to "not" a value or parameter generally indicates and describes "other than" a value or parameter. For example, the method cannot be used to treat type X cancer, which means that the method is generally used to treat other types of cancer except type X cancer.

[0123] As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0124] Anti-FXIIa Antibodies

[0125] On the one hand, the present application provides anti-human or / and rhesus monkey FXIIa antibodies that specifically bind to FXIIa. The anti-FXIIa antibodies include, but are not limited to, humanized antibodies, chimeric antibodies, mouse antibodies, human antibodies, and antibody molecules comprising heavy chain and / or light chain CDRs as described herein. On the one hand, the present application provides antibodies separated from FXIIa. Expected anti-FXIIa antibodies include, for example, full-length anti-FXIIa antibodies (such as full-length IgG1 or IgG4), anti-FXIIa single-chain antibodies, anti-FXIIaFc fusion proteins, multi-specific (such as bispecific) anti-FXIIa antibodies, anti-FXIIa immunoconjugates, and the like. In certain embodiments, the anti-FXIIa antibody is a full-length antibody (such as full-length IgG1 or IgG4) or an antigen-binding fragment thereof, which specifically binds to FXIIa. In some embodiments, the anti-FXIIa antibody is Fab, Fab', F(ab)'2, Fab'-SH, single-chain Fv (scFv), Fv fragment, dAb, Fd, nanobody, double-chain antibody (diabody) or linear antibody. In some embodiments, the antibody that specifically binds to FXIIa refers to an antibody that binds to FXIIa with an affinity that is at least 10 times greater than the affinity for binding to a non-target (including, for example, 10, 10 2 , 10 3 , 10 4 , 10 5 , 10 6 , or 10 7 In some embodiments, non-target refers to an antigen that is not FXIIa. Binding affinity can be determined by methods known in the art, such as ELISA, fluorescence activated cell sorting (FACS) analysis or radioimmunoprecipitation analysis (RIA). Kd values ​​can be determined by methods known in the art, such as surface plasmon resonance (SPR) technology or biolayer interferometry (BLI).

[0126] Although anti-FXIIa antibodies comprising human sequences (e.g., human heavy and light chain variable domains comprising human CDR sequences) are discussed extensively herein, non-human anti-FXIIa antibodies are also contemplated. In some embodiments, non-human anti-FXIIa antibodies include human CDR sequences and non-human framework sequences of anti-FXIIa antibodies described herein, and in some embodiments, non-human framework sequences include any sequence for generating heavy and / or light chain variable domains using one or more human CDR sequences as described herein, including, for example, mammals, such as mice, rats, rabbits, pigs, cattle (e.g., cattle, bulls, buffaloes), deer, sheep, goats, chickens, cats, dogs, ferrets, primates (e.g., small apes, macaques), etc. In some embodiments, non-human anti-FXIIa antibodies include anti-FXIIa antibodies generated by grafting one or more human CDR sequences described herein into non-human framework sequences (e.g., mouse or chicken framework sequences).

[0127] The complete amino acid sequence of an exemplary human FXII comprises or consists of the amino acid sequence shown in SEQ ID NO:111.

[0128] In some embodiments, the anti-FXIIa antibodies described herein specifically recognize an epitope in human FXIIa. In some embodiments, the anti-FXIIa antibodies cross-react with FXIIa of species other than human. In some embodiments, the anti-FXIIa antibodies are completely specific for human FXIIa and do not cross-react with other non-human species.

[0129] In some embodiments, the anti-FXIIa antibody cross-reacts with at least one allelic variant of the FXIIa protein (or a fragment thereof). In some embodiments, the allelic variant has up to 30 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, or 30) amino acid substitutions (e.g., conservative substitutions) compared to the naturally occurring FXIIa protein (or a fragment thereof). In some embodiments, the anti-FXIIa antibody does not cross-react with any allelic variant of the FXIIa protein (or a fragment thereof).

[0130] In some embodiments, the anti-FXIIa antibody cross-reacts with at least one interspecies variant of the FXIIa protein. In some embodiments, for example, the FXIIa protein (or its fragment) is human FXIIa, and the interspecies variant of the FXIIa protein (or its fragment) is a variant in cynomolgus monkeys. In some embodiments, the anti-FXIIa antibody does not cross-react with any interspecies variant of the FXIIa protein.

[0131] In some embodiments, as any anti-FXIIa antibody described herein, the anti-FXIIa antibody comprises an antibody heavy chain constant region and an antibody light chain constant region. In some embodiments, the anti-FXIIa antibody comprises an IgG1-type heavy chain constant region. In some embodiments, the anti-FXIIa antibody comprises an IgG2-type heavy chain constant region. In some embodiments, the anti-FXIIa antibody comprises an IgG3-type heavy chain constant region. In some embodiments, the anti-FXIIa antibody comprises an IgG4-type heavy chain constant region. In some embodiments, the heavy chain constant region comprises (including consisting of or consisting essentially of) the amino acid sequence SEQ ID NO: 107. In some embodiments, the heavy chain constant region comprises (including consisting of or consisting essentially of) the amino acid sequence SEQ ID NO: 108. In some embodiments, the anti-FXIIa antibody comprises a kappa light chain constant region. In some embodiments, the light chain constant region comprises (including consisting of or consisting essentially of) the amino acid sequence SEQ ID NO: 109. In some embodiments, the anti-FXIIa antibody comprises a lambda light chain constant region. In some embodiments, the light chain constant region comprises (including consisting of or consisting essentially of) the amino acid sequence SEQ ID NO: 110. In some embodiments, the anti-FXIIa antibody comprises an antibody heavy chain variable domain and an antibody light chain variable domain.

[0132] In some embodiments, the anti-FXIIa antibody comprises V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 10, HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 22, or the V H A variant of V comprising substitutions of up to about 5 amino acids in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 34, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 48, LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 56, or the V L A variant comprising substitutions of up to about 5 amino acids in the LC-CDRs.

[0133] In some embodiments, the anti-FXIIa antibody comprises V H , the V Hcomprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 10, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 22; and V L , the V L It comprises: LC-CDR1, which comprises the amino acid sequence of SEQ ID NO:34, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:48, and LC-CDR3, which comprises the amino acid sequence of SEQ ID NO:56.

[0134] In some embodiments, the anti-FXIIa antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO:73 H HC-CDR1, HC-CDR2 and HC-CDR3; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:90 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0135] In some embodiments, the anti-FXIIa antibody comprises: H , the V H comprising the amino acid sequence of SEQ ID NO:73 or a variant thereof, said variant having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO:73; and V L , the V L The invention relates to an anti-FXIIa antibody comprising an amino acid sequence of SEQ ID NO: 90 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 90. In some embodiments, the anti-FXIIa antibody comprises V H , the V H Comprising the amino acid sequence SEQ ID NO:73, and V L , the V L Comprising the amino acid sequence SEQ ID NO:90.

[0136] In some embodiments, the anti-FXIIa antibody comprises V H , the V Hcomprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 11, HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 23, or the V H A variant of V comprising substitutions of up to about 5 amino acids in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO:35, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:49, LC-CDR3 comprising the amino acid sequence of SEQ ID NO:57, or the V L A variant comprising substitutions of up to about 5 amino acids in the LC-CDRs.

[0137] In some embodiments, the anti-FXIIa antibody comprises V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 11, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 23; and V L , the V L It comprises: LC-CDR1, which comprises the amino acid sequence of SEQ ID NO:35, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:49, and LC-CDR3, which comprises the amino acid sequence of SEQ ID NO:57.

[0138] In some embodiments, the anti-FXIIa antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO:74 H HC-CDR1, HC-CDR2 and HC-CDR3; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:91 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0139] In some embodiments, the anti-FXIIa antibody comprises: H , the V H comprising the amino acid sequence of SEQ ID NO:74 or a variant thereof, the variant having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO:74; and V L , the VL The invention relates to an anti-FXIIa antibody comprising an amino acid sequence of SEQ ID NO: 91 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 91. In some embodiments, the anti-FXIIa antibody comprises V H , the V H Comprising the amino acid sequence SEQ ID NO:74, and V L , the V L Comprising the amino acid sequence SEQ ID NO:91.

[0140] In some embodiments, the anti-FXIIa antibody comprises V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 2, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 12, HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 24, or the V H A variant of V comprising substitutions of up to about 5 amino acids in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO:36, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:50, LC-CDR3 comprising the amino acid sequence of SEQ ID NO:58, or the V L A variant comprising substitutions of up to about 5 amino acids in the LC-CDRs.

[0141] In some embodiments, the anti-FXIIa antibody comprises V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 2, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 12, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 24; and V L , the V L It comprises: LC-CDR1, which comprises the amino acid sequence of SEQ ID NO:36, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:50, and LC-CDR3, which comprises the amino acid sequence of SEQ ID NO:58.

[0142] In some embodiments, the anti-FXIIa antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO:75 HHC-CDR1, HC-CDR2 and HC-CDR3; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:92 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0143] In some embodiments, the anti-FXIIa antibody comprises: H , the V H comprising the amino acid sequence of SEQ ID NO:75 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO:75; and V L , the V L The invention relates to an anti-FXIIa antibody comprising an amino acid sequence of SEQ ID NO: 92 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 92. In some embodiments, the anti-FXIIa antibody comprises V H , the V H Comprising the amino acid sequence SEQ ID NO:75, and V L , the V L Comprising the amino acid sequence SEQ ID NO:92.

[0144] In some embodiments, the anti-FXIIa antibody comprises V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 3, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 13, HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 25, or the V H A variant of V comprising substitutions of up to about 5 amino acids in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 37, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 51, LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 59, or the V L A variant comprising substitutions of up to about 5 amino acids in the LC-CDRs.

[0145] In some embodiments, the anti-FXIIa antibody comprises V H , the V Hcomprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 3, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 13, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 25; and V L , the V L It comprises: LC-CDR1, which comprises the amino acid sequence of SEQ ID NO:37, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:51, and LC-CDR3, which comprises the amino acid sequence of SEQ ID NO:59.

[0146] In some embodiments, the anti-FXIIa antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO:76 H HC-CDR1, HC-CDR2 and HC-CDR3; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:93 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0147] In some embodiments, the anti-FXIIa antibody comprises: H , the V H comprising the amino acid sequence of SEQ ID NO:76 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO:76; and V L , the V L The invention relates to an anti-FXIIa antibody comprising an amino acid sequence of SEQ ID NO: 93 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 93. In some embodiments, the anti-FXIIa antibody comprises V H , the V H Comprising the amino acid sequence SEQ ID NO:76, and V L , the V L Comprising the amino acid sequence SEQ ID NO:93.

[0148] In some embodiments, the anti-FXIIa antibody comprises V H , the V Hcomprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 4, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 14, HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 26, or the V H A variant of V comprising substitutions of up to about 5 amino acids in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 37, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 51, LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 60, or the V L A variant comprising substitutions of up to about 5 amino acids in the LC-CDRs.

[0149] In some embodiments, the anti-FXIIa antibody comprises V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 4, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 14, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 26; and V L , the V L It comprises: LC-CDR1, which comprises the amino acid sequence of SEQ ID NO:37, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:51, and LC-CDR3, which comprises the amino acid sequence of SEQ ID NO:60.

[0150] In some embodiments, the anti-FXIIa antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO:77 H HC-CDR1, HC-CDR2 and HC-CDR3; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:94 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0151] In some embodiments, the anti-FXIIa antibody comprises: H , the V H comprising the amino acid sequence of SEQ ID NO:77 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO:77; and V L , the VL The invention relates to an anti-FXIIa antibody comprising an amino acid sequence of SEQ ID NO: 94 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 94. In some embodiments, the anti-FXIIa antibody comprises V H , the V H Comprising the amino acid sequence SEQ ID NO:77, and V L , the V L Comprising the amino acid sequence SEQ ID NO:94.

[0152] In some embodiments, the anti-FXIIa antibody comprises V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 3, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 13, HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 25, or the V H A variant of V comprising substitutions of up to about 5 amino acids in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 37, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 51, LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 61, or the V L A variant comprising substitutions of up to about 5 amino acids in the LC-CDRs.

[0153] In some embodiments, the anti-FXIIa antibody comprises V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 3, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 13, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 25; and V L , the V L It comprises: LC-CDR1, which comprises the amino acid sequence of SEQ ID NO:37, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:51, and LC-CDR3, which comprises the amino acid sequence of SEQ ID NO:61.

[0154] In some embodiments, the anti-FXIIa antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO:78 HHC-CDR1, HC-CDR2 and HC-CDR3; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:95 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0155] In some embodiments, the anti-FXIIa antibody comprises: H , the V H comprising the amino acid sequence of SEQ ID NO:78 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO:78; and V L , the V L The invention relates to an anti-FXIIa antibody comprising an amino acid sequence of SEQ ID NO: 95 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 95. In some embodiments, the anti-FXIIa antibody comprises V H , the V H Comprising the amino acid sequence SEQ ID NO:78, and V L , the V L Comprising the amino acid sequence SEQ ID NO:95.

[0156] In some embodiments, the anti-FXIIa antibody comprises V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 2, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 12, HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 24, or the V H A variant of V comprising substitutions of up to about 5 amino acids in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 38, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 50, LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 62, or the V L A variant comprising substitutions of up to about 5 amino acids in the LC-CDRs.

[0157] In some embodiments, the anti-FXIIa antibody comprises V H , the V Hcomprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 2, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 12, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 24; and V L , the V L It comprises: LC-CDR1, which comprises the amino acid sequence of SEQ ID NO:38, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:50, and LC-CDR3, which comprises the amino acid sequence of SEQ ID NO:62.

[0158] In some embodiments, the anti-FXIIa antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO:79 H HC-CDR1, HC-CDR2 and HC-CDR3; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:96 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0159] In some embodiments, the anti-FXIIa antibody comprises: H , the V H comprising the amino acid sequence of SEQ ID NO:79 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO:79; and V L , the V L The invention relates to an anti-FXIIa antibody comprising an amino acid sequence of SEQ ID NO: 96 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 96. In some embodiments, the anti-FXIIa antibody comprises V H , the V H Comprising the amino acid sequence SEQ ID NO:79, and V L , the V L Comprising the amino acid sequence SEQ ID NO:96.

[0160] In some embodiments, the anti-FXIIa antibody comprises V H , the V Hcomprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 3, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 13, HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 25, or the V H A variant of V comprising substitutions of up to about 5 amino acids in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 39, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 52, LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 63, or the V L A variant comprising substitutions of up to about 5 amino acids in the LC-CDRs.

[0161] In some embodiments, the anti-FXIIa antibody comprises V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 3, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 13, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 25; and V L , the V L It comprises: LC-CDR1, which comprises the amino acid sequence of SEQ ID NO:39, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:52, and LC-CDR3, which comprises the amino acid sequence of SEQ ID NO:63.

[0162] In some embodiments, the anti-FXIIa antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO:80 H HC-CDR1, HC-CDR2 and HC-CDR3; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:97 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0163] In some embodiments, the anti-FXIIa antibody comprises: H , the V H comprising the amino acid sequence of SEQ ID NO: 80 or a variant thereof, the variant having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 80; and V L , the VL The invention relates to an anti-FXIIa antibody comprising an amino acid sequence of SEQ ID NO: 97 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 97. In some embodiments, the anti-FXIIa antibody comprises V H , the V H Comprising the amino acid sequence SEQ ID NO:80, and V L , the V L Comprising the amino acid sequence SEQ ID NO:97.

[0164] In some embodiments, the anti-FXIIa antibody comprises V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 10, HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 27, or the V H A variant of V comprising substitutions of up to about 5 amino acids in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO:40, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:53, LC-CDR3 comprising the amino acid sequence of SEQ ID NO:64, or the V L A variant comprising substitutions of up to about 5 amino acids in the LC-CDRs.

[0165] In some embodiments, the anti-FXIIa antibody comprises V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 10, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 27; and V L , the V L It comprises: LC-CDR1, which comprises the amino acid sequence of SEQ ID NO:40, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:53, and LC-CDR3, which comprises the amino acid sequence of SEQ ID NO:64.

[0166] In some embodiments, the anti-FXIIa antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO:81 HHC-CDR1, HC-CDR2 and HC-CDR3; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:98 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0167] In some embodiments, the anti-FXIIa antibody comprises: H , the V H comprising the amino acid sequence of SEQ ID NO:81 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO:81; and V L , the V L The invention relates to an anti-FXIIa antibody comprising an amino acid sequence of SEQ ID NO: 98 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 98. In some embodiments, the anti-FXIIa antibody comprises V H , the V H Comprising the amino acid sequence SEQ ID NO:81, and V L , the V L Comprising the amino acid sequence SEQ ID NO:98.

[0168] In some embodiments, the anti-FXIIa antibody comprises V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 5, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 15, HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 28, or the V H A variant of V comprising substitutions of up to about 5 amino acids in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO:41, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:50, LC-CDR3 comprising the amino acid sequence of SEQ ID NO:65, or the V L A variant comprising substitutions of up to about 5 amino acids in the LC-CDRs.

[0169] In some embodiments, the anti-FXIIa antibody comprises V H , the V Hcomprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 5, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 15, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 28; and V L , the V L It comprises: LC-CDR1, which comprises the amino acid sequence of SEQ ID NO:41, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:50, and LC-CDR3, which comprises the amino acid sequence of SEQ ID NO:65.

[0170] In some embodiments, the anti-FXIIa antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO:82 H HC-CDR1, HC-CDR2 and HC-CDR3; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:99 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0171] In some embodiments, the anti-FXIIa antibody comprises: H , the V H comprising the amino acid sequence of SEQ ID NO:82 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO:82; and V L , the V L The invention relates to an anti-FXIIa antibody comprising an amino acid sequence of SEQ ID NO: 99 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 99. In some embodiments, the anti-FXIIa antibody comprises V H , the V H Comprising the amino acid sequence SEQ ID NO:82, and V L , the V L Comprising the amino acid sequence SEQ ID NO:99.

[0172] In some embodiments, the anti-FXIIa antibody comprises V H , the V Hcomprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 6, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 16, HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 29, or the V H A variant of V comprising substitutions of up to about 5 amino acids in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO:42, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:54, LC-CDR3 comprising the amino acid sequence of SEQ ID NO:66, or the V L A variant comprising substitutions of up to about 5 amino acids in the LC-CDRs.

[0173] In some embodiments, the anti-FXIIa antibody comprises V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 6, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 16, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 29; and V L , the V L It comprises: LC-CDR1, which comprises the amino acid sequence of SEQ ID NO:42, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:54, and LC-CDR3, which comprises the amino acid sequence of SEQ ID NO:66.

[0174] In some embodiments, the anti-FXIIa antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO:83 H HC-CDR1, HC-CDR2 and HC-CDR3; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO: 100 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0175] In some embodiments, the anti-FXIIa antibody comprises: H , the V H comprising the amino acid sequence of SEQ ID NO:83 or a variant thereof, said variant having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO:83; and V L , the VL The invention relates to an anti-FXIIa antibody comprising an amino acid sequence of SEQ ID NO: 100 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 100. In some embodiments, the anti-FXIIa antibody comprises V H , the V H Comprising the amino acid sequence SEQ ID NO:83, and V L , the V L Comprising the amino acid sequence SEQ ID NO:100.

[0176] In some embodiments, the anti-FXIIa antibody comprises V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 6, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 17, HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 30, or the V H A variant of V comprising substitutions of up to about 5 amino acids in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO:43, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:50, LC-CDR3 comprising the amino acid sequence of SEQ ID NO:67, or the V L A variant comprising substitutions of up to about 5 amino acids in the LC-CDRs.

[0177] In some embodiments, the anti-FXIIa antibody comprises V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 6, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 17, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 30; and V L , the V L It comprises: LC-CDR1, which comprises the amino acid sequence of SEQ ID NO:43, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:50, and LC-CDR3, which comprises the amino acid sequence of SEQ ID NO:67.

[0178] In some embodiments, the anti-FXIIa antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO:84 HHC-CDR1, HC-CDR2 and HC-CDR3; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:101 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0179] In some embodiments, the anti-FXIIa antibody comprises: H , the V H comprising the amino acid sequence of SEQ ID NO:84 or a variant thereof, said variant having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO:84; and V L , the V L The invention relates to an anti-FXIIa antibody comprising an amino acid sequence of SEQ ID NO: 101 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 101. In some embodiments, the anti-FXIIa antibody comprises V H , the V H Comprising the amino acid sequence SEQ ID NO:84, and V L , the V L Comprising the amino acid sequence SEQ ID NO:101.

[0180] In some embodiments, the anti-FXIIa antibody comprises V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 5, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 15, HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 28, or the V H A variant of V comprising substitutions of up to about 5 amino acids in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO:44, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:50, LC-CDR3 comprising the amino acid sequence of SEQ ID NO:68, or the V L A variant comprising substitutions of up to about 5 amino acids in the LC-CDRs.

[0181] In some embodiments, the anti-FXIIa antibody comprises V H , the V Hcomprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 5, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 15, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 28; and V L , the V L It comprises: LC-CDR1, which comprises the amino acid sequence of SEQ ID NO:44, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:50, and LC-CDR3, which comprises the amino acid sequence of SEQ ID NO:68.

[0182] In some embodiments, the anti-FXIIa antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO:85 H HC-CDR1, HC-CDR2 and HC-CDR3; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:102 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0183] In some embodiments, the anti-FXIIa antibody comprises: H , the V H comprising the amino acid sequence of SEQ ID NO:85 or a variant thereof, said variant having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO:85; and V L , the V L The invention relates to an anti-FXIIa antibody comprising an amino acid sequence of SEQ ID NO: 102 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 102. In some embodiments, the anti-FXIIa antibody comprises V H , the V H Comprising the amino acid sequence SEQ ID NO:85, and V L , the V L Comprising the amino acid sequence SEQ ID NO:102.

[0184] In some embodiments, the anti-FXIIa antibody comprises V H , the V Hcomprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 7, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 18, HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 31, or the V H A variant of V comprising substitutions of up to about 5 amino acids in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO:45, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:55, LC-CDR3 comprising the amino acid sequence of SEQ ID NO:69, or the V L A variant comprising substitutions of up to about 5 amino acids in the LC-CDRs.

[0185] In some embodiments, the anti-FXIIa antibody comprises V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 7, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 18, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 31; and V L , the V L It comprises: LC-CDR1, which comprises the amino acid sequence of SEQ ID NO:45, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:55, and LC-CDR3, which comprises the amino acid sequence of SEQ ID NO:69.

[0186] In some embodiments, the anti-FXIIa antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO:86 H HC-CDR1, HC-CDR2 and HC-CDR3; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:103 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0187] In some embodiments, the anti-FXIIa antibody comprises: H , the V H comprising the amino acid sequence of SEQ ID NO:86 or a variant thereof, said variant having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO:86; and V L , the VL The invention relates to an anti-FXIIa antibody comprising an amino acid sequence of SEQ ID NO: 103 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 103. In some embodiments, the anti-FXIIa antibody comprises V H , the V H Comprising the amino acid sequence SEQ ID NO:86, and V L , the V L Comprising the amino acid sequence SEQ ID NO:103.

[0188] In some embodiments, the anti-FXIIa antibody comprises V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 8, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 19, HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 28, or the V H A variant of V comprising substitutions of up to about 5 amino acids in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO:46, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:50, LC-CDR3 comprising the amino acid sequence of SEQ ID NO:70, or the V L A variant comprising substitutions of up to about 5 amino acids in the LC-CDRs.

[0189] In some embodiments, the anti-FXIIa antibody comprises V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 8, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 19, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 28; and V L , the V L It comprises: LC-CDR1, which comprises the amino acid sequence of SEQ ID NO:46, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:50, and LC-CDR3, which comprises the amino acid sequence of SEQ ID NO:70.

[0190] In some embodiments, the anti-FXIIa antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO:87 HHC-CDR1, HC-CDR2 and HC-CDR3; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO: 104 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0191] In some embodiments, the anti-FXIIa antibody comprises: H , the V H comprising the amino acid sequence of SEQ ID NO:87 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO:87; and V L , the V L The invention relates to an anti-FXIIa antibody comprising an amino acid sequence of SEQ ID NO: 104 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 104. In some embodiments, the anti-FXIIa antibody comprises V H , the V H Comprising the amino acid sequence SEQ ID NO:87, and V L , the V L Comprising the amino acid sequence SEQ ID NO:104.

[0192] In some embodiments, the anti-FXIIa antibody comprises V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 9, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 20, HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 32, or the V H A variant of V comprising substitutions of up to about 5 amino acids in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO:47, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:51, LC-CDR3 comprising the amino acid sequence of SEQ ID NO:71, or the V L A variant comprising substitutions of up to about 5 amino acids in the LC-CDRs.

[0193] In some embodiments, the anti-FXIIa antibody comprises V H , the V Hcomprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 9, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 20, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 32; and V L , the V L It comprises: LC-CDR1, which comprises the amino acid sequence of SEQ ID NO:47, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:51, and LC-CDR3, which comprises the amino acid sequence of SEQ ID NO:71.

[0194] In some embodiments, the anti-FXIIa antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO:88 H HC-CDR1, HC-CDR2 and HC-CDR3; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO: 105 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0195] In some embodiments, the anti-FXIIa antibody comprises: H , the V H comprising the amino acid sequence of SEQ ID NO:88 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO:88; and V L , the V L The invention relates to an anti-FXIIa antibody comprising an amino acid sequence of SEQ ID NO: 105 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 105. In some embodiments, the anti-FXIIa antibody comprises V H , the V H Comprising the amino acid sequence SEQ ID NO: 88, and V L , the V L Comprising the amino acid sequence SEQ ID NO:105.

[0196] In some embodiments, the anti-FXIIa antibody comprises V H , the V Hcomprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 3, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 21, HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 33, or the V H A variant of V comprising substitutions of up to about 5 amino acids in its HC-CDRs; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 37, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 51, LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 72, or the V L A variant comprising substitutions of up to about 5 amino acids in the LC-CDRs.

[0197] In some embodiments, the anti-FXIIa antibody comprises V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 3, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 21, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 33; and V L , the V L It comprises: LC-CDR1, which comprises the amino acid sequence of SEQ ID NO:37, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:51, and LC-CDR3, which comprises the amino acid sequence of SEQ ID NO:72.

[0198] In some embodiments, the anti-FXIIa antibody comprises V H , which comprises V as shown in the amino acid sequence SEQ ID NO:89 H HC-CDR1, HC-CDR2 and HC-CDR3; and V L , which comprises V as shown in the amino acid sequence SEQ ID NO:106 L Contains LC-CDR1, LC-CDR2 and LC-CDR3.

[0199] In some embodiments, the anti-FXIIa antibody comprises: H , the V H comprising the amino acid sequence of SEQ ID NO:89 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO:89; and V L , the VL The invention relates to an anti-FXIIa antibody comprising an amino acid sequence of SEQ ID NO: 106 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 106. In some embodiments, the anti-FXIIa antibody comprises V H , the V H Comprising the amino acid sequence SEQ ID NO: 89, and V L , the V L Comprising the amino acid sequence SEQ ID NO:106.

[0200] In some embodiments, the above-mentioned amino acid substitutions are limited to the "exemplary substitutions" shown in Table 4 herein. In some embodiments, the amino acid substitutions are limited to the "preferred substitutions" shown in Table 4 herein.

[0201] In some embodiments, functional epitopes can be resolved by combined alanine scanning. In this process, combined alanine scanning technology can be used to identify amino acids in the FXIIa protein that are necessary for interaction with anti-FXIIa antibodies. In some embodiments, the epitope is conformational and the crystal structure of the anti-FXIIa antibody bound to the FXIIa protein can be used to identify the epitope.

[0202] In some embodiments, the present application provides antibodies that competitively bind to FXIIa with any of the anti-FXIIa antibodies described herein. In some embodiments, antibodies that can competitively bind to an epitope on FXIIa with any of the anti-FXIIa antibodies described herein are provided. In some embodiments, anti-FXIIa antibodies are provided that are combined with a V H and V L The anti-FXIIa antibody molecules bind to the same epitope, wherein the V H comprising an amino acid sequence as shown in any one of SEQ ID NOs:73-89, and said V L In some embodiments, an anti-FXIIa antibody is provided, which is combined with a V H and V L The anti-FXIIa antibody competitively binds to FXIIa, wherein the V H comprising an amino acid sequence as shown in any one of SEQ ID NOs:73-89, and said V L It comprises the amino acid sequence shown in any one of SEQ ID NOs:90-106.

[0203] In some embodiments, competition experiments can be used to identify monoclonal antibodies that compete with the anti-FXIIa antibodies described herein for binding to FXIIa. Competition experiments can determine whether two antibodies bind to the same epitope by recognizing the same or spatially overlapping epitopes or by one antibody competitively inhibiting the binding of another antibody to the antigen. In certain embodiments, such a competing antibody binds to the same epitope as the antibody described herein. Some exemplary competition experiments include, but are not limited to, routine experiments as described in Harlow and Lane (1988) Antibodies: A Laboratory Manual ch.14 (Cold Spring Harbor Laboratory, Cold Spring Harbor, NY). Detailed exemplary methods for parsing epitopes bound by antibodies are described in Morris (1996) "Epitope Mapping Protocols," in Methods in Molecular Biology vol.66 (Humana Press, Totowa, NJ). In some embodiments, if each antibody blocks 50% or more of the binding of another antibody, it is said to bind to the same epitope. In some embodiments, the antibody that competes with the anti-FXIIa antibody described herein is a chimeric antibody, a humanized antibody, or a fully human antibody.

[0204] Exemplary anti-FXIIa antibody sequences are shown in Tables 2 and 3, wherein CDR numbering is performed according to the Kabat definition. Those skilled in the art will recognize that there are a variety of known algorithms for predicting the position of CDRs and defining antibody light and heavy chain variable regions. H and / or V L Sequences, but based on prediction algorithms other than the antibodies exemplified in the table below are also within the scope of the present application.

[0205] Table 2A Exemplary anti-FXIIa antibody CDR sequences

[0206]

[0207]

[0208] Table 2B Exemplary anti-FXIIa antibody CDR sequences

[0209]

[0210] Table 3A Exemplary sequences

[0211]

[0212]

[0213]

[0214] Table 3B Exemplary sequences

[0215]

[0216]

[0217] FXIIa

[0218] There are two convergent pathways of coagulation that are triggered by either extrinsic (vessel wall) or intrinsic (blood-borne) components of the vascular system. The extrinsic pathway is initiated by a complex of factor VII (FVII) with the membrane-intrinsic protein tissue factor (TF). TF expressed in circulating microvesicles may also promote thrombus propagation by maintaining thrombin generation on the surface of activated platelets. The intrinsic or contact-activated pathway is initiated when FXII comes into contact with a negatively charged surface in a reaction. Robert Colman first referred to FXII and contact activation as a surface-activated defense mechanism to describe contact activation that occurs with foreign pathogens (e.g., bacteria, viruses, yeast, parasites) or artificial surfaces (e.g., glass, medical devices) (Colman RW et al., 1997, Blood; 90:3819–43.). FXII has the unique property of autoactivating from a zymogen to an active enzyme. When the zymogen is incubated alone with a negatively charged surface, the autoactivation process of FXII is slow (90-120 minutes). When FXII is incubated with HK and PK or in plasma, the autoactivation process is greatly accelerated. FXIIa is a serine protease whose substrates include PK, FXI, plasminogen, complement component 1r (C1r), C1s, and HK. FXIIa activates PK to pKal, resulting in a state of mutual activation of pKal to FXII, and the formed FXIIa activates more PK, thereby amplifying the activity of the system. HK stabilizes PK to obtain optimal activation of FXIIa. Autoactivation, mutual activation, and amplification are the essence of the contact activation system (CAS) (Tankersley DL et al., 1984, Biochemistry; 23: 273–9.). The formation of pKal by FXIIa activation or other means means the initiation of the so-called kallikrein-kinin system. pKal cleaves HK to release bradykinin and kininogen fragments (i.e., cHK). Bradykinin affects vascular permeability by binding to the G protein-coupled receptor bradykinin B2 and B1 receptors. FXIIa activates FXI to initiate contact activation of coagulation. FXIIa activates plasminogen, and C1r / C1s initiates fibrinolysis and classical complement activation, respectively.

[0219] Full-length anti-FXIIa antibody

[0220] In some embodiments, the anti-FXIIa antibody is a full-length anti-FXIIa antibody. In some embodiments, the full-length anti-FXIIa antibody is IgA, IgD, IgE, IgG or IgM. In some embodiments, the full-length anti-FXIIa antibody comprises an IgG constant region, such as a constant region of IgG1, IgG2, IgG3, IgG4 or a variant thereof. In some embodiments, the full-length anti-FXIIa antibody comprises a λ light chain constant region. In some embodiments, the full-length anti-FXIIa antibody comprises a κ light chain constant region. In some embodiments, the full-length anti-FXIIa antibody is a full-length human anti-FXIIa antibody. In some embodiments, the full-length anti-FXIIa antibody comprises a mouse immunoglobulin Fc sequence. In some embodiments, the full-length anti-FXIIa antibody comprises an Fc sequence that has been altered or otherwise altered so that it has enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) effector functions.

[0221] Thus, for example, in some embodiments, a full-length anti-FXIIa antibody comprising an IgG1 constant region is provided, wherein the anti-FXIIa antibody specifically binds to FXIIa. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 107. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 107 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 107 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 110.

[0222] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG2 constant region is provided, wherein the anti-FXIIa antibody specifically binds to FXIIa. In some embodiments, the IgG2 is human IgG2. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 110.

[0223] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG3 constant region is provided, wherein the anti-FXIIa antibody specifically binds to FXIIa. In some embodiments, the IgG3 is a human IgG3. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 110.

[0224] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG4 constant region is provided, and the anti-FXIIa antibody specifically binds to FXIIa. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 108. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 108 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 108 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 110.

[0225] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG1 constant region is provided, wherein the anti-FXIIa antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1, which comprises an amino acid sequence as shown in any one of SEQ ID NOs: 1-9 or a variant thereof, wherein the variant comprises a substitution of up to about 3 (e.g., 1, 2 or 3) amino acids; HC-CDR2, which comprises an amino acid sequence as shown in any one of SEQ ID NOs: 10-21 or a variant thereof, wherein the variant comprises a substitution of up to about 3 (e.g., 1, 2 or 3) amino acids; and HC-CDR3, which comprises an amino acid sequence as shown in any one of SEQ ID NOs: 22-33 or a variant thereof, wherein the variant comprises a substitution of up to about 3 (e.g., 1, 2 or 3) amino acids; and b) a light chain variable domain, the light chain variable domain comprising: LC-CDR1, which comprises SEQ ID NOs: NOs:34-47 or a variant thereof, the variant comprising a substitution of up to about 3 (e.g., 1, 2, or 3) amino acids, LC-CDR2, which comprises an amino acid sequence as shown in any one of SEQ ID NOs:48-55 or a variant thereof, the variant comprising a substitution of up to about 3 (e.g., 1, 2, or 3) amino acids; and LC-CDR3, which comprises an amino acid sequence as shown in any one of SEQ ID NOs:56-72 or a variant thereof, the variant comprising a substitution of up to about 3 (e.g., 1, 2, or 3) amino acids. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:107. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:107 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:110.

[0226] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG2 constant region is provided, wherein the anti-FXIIa antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1, which comprises an amino acid sequence as shown in any one of SEQ ID NOs: 1-9 or a variant thereof, wherein the variant comprises a substitution of up to about 3 (e.g., 1, 2 or 3) amino acids; HC-CDR2, which comprises an amino acid sequence as shown in any one of SEQ ID NOs: 10-21 or a variant thereof, wherein the variant comprises a substitution of up to about 3 (e.g., 1, 2 or 3) amino acids; and HC-CDR3, which comprises an amino acid sequence as shown in any one of SEQ ID NOs: 22-33 or a variant thereof, wherein the variant comprises a substitution of up to about 3 (e.g., 1, 2 or 3) amino acids; and b) a light chain variable domain, the light chain variable domain comprising: LC-CDR1, which comprises SEQ ID NOs: NOs:34-47 or a variant thereof, the variant comprising a substitution of up to about 3 (e.g., 1, 2, or 3) amino acids; LC-CDR2, which comprises an amino acid sequence as shown in any one of SEQ ID NOs:48-55 or a variant thereof, the variant comprising a substitution of up to about 3 (e.g., 1, 2, or 3) amino acids; and LC-CDR3, which comprises an amino acid sequence as shown in any one of SEQ ID NOs:56-72 or a variant thereof, the variant comprising a substitution of up to about 3 (e.g., 1, 2, or 3) amino acids. In some embodiments, the IgG2 is a human IgG2. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:110.

[0227] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG3 constant region is provided, wherein the anti-FXIIa antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1, which comprises an amino acid sequence as shown in any one of SEQ ID NOs: 1-9 or a variant thereof, wherein the variant comprises a substitution of up to about 3 (e.g., 1, 2 or 3) amino acids, HC-CDR2, which comprises an amino acid sequence as shown in any one of SEQ ID NOs: 10-21 or a variant thereof, wherein the variant comprises a substitution of up to about 3 (e.g., 1, 2 or 3) amino acids; and HC-CDR3, which comprises an amino acid sequence as shown in any one of SEQ ID NOs: 22-33 or a variant thereof, wherein the variant comprises a substitution of up to about 3 (e.g., 1, 2 or 3) amino acids; and b) a light chain variable domain, the light chain variable domain comprising: LC-CDR1, which comprises SEQ ID NOs: NOs:34-47 or a variant thereof, the variant comprising a substitution of up to about 3 (e.g., 1, 2, or 3) amino acids; LC-CDR2, which comprises an amino acid sequence as shown in any one of SEQ ID NOs:48-55 or a variant thereof, the variant comprising a substitution of up to about 3 (e.g., 1, 2, or 3) amino acids; and LC-CDR3, which comprises an amino acid sequence as shown in any one of SEQ ID NOs:56-72 or a variant thereof, the variant comprising a substitution of up to about 3 (e.g., 1, 2, or 3) amino acids. In some embodiments, the IgG3 is a human IgG3. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:110.

[0228] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG4 constant region is provided, wherein the anti-FXIIa antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1, which comprises an amino acid sequence as shown in any one of SEQ ID NOs: 1-9 or a variant thereof, wherein the variant comprises a substitution of up to about 3 (e.g., 1, 2 or 3) amino acids; HC-CDR2, which comprises an amino acid sequence as shown in any one of SEQ ID NOs: 10-21 or a variant thereof, wherein the variant comprises a substitution of up to about 3 (e.g., 1, 2 or 3) amino acids; and HC-CDR3, which comprises an amino acid sequence as shown in any one of SEQ ID NOs: 22-33 or a variant thereof, wherein the variant comprises a substitution of up to about 3 (e.g., 1, 2 or 3) amino acids; and b) a light chain variable domain, the light chain variable domain comprising: LC-CDR1, which comprises SEQ ID NOs: NOs:34-47 or a variant thereof, the variant comprising a substitution of up to about 3 (e.g., 1, 2 or 3) amino acids, LC-CDR2, which comprises an amino acid sequence as shown in any one of SEQ ID NOs:48-55 or a variant thereof, the variant comprising a substitution of up to about 3 (e.g., 1, 2 or 3) amino acids, and LC-CDR3, which comprises an amino acid sequence as shown in any one of SEQ ID NOs:56-72 or a variant thereof, the variant comprising a substitution of up to about 3 (e.g., 1, 2 or 3) amino acids. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:108. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:108 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:110.

[0229] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG1 constant region is provided, wherein the anti-FXIIa antibody comprises: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence shown in any one of SEQ ID NOs: 1-9, HC-CDR2 comprising the amino acid sequence shown in any one of SEQ ID NOs: 10-21, and HC-CDR3 comprising the amino acid sequence shown in any one of SEQ ID NOs: 22-33, or a variant of the heavy chain variable domain, wherein the HC-CDR sequence comprises up to about 5 (e.g., 1, 2, 3, 4 or 5) amino acid substitutions; and b) a light chain variable domain, the light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence shown in any one of SEQ ID NOs: 34-47, LC-CDR2 comprising the amino acid sequence shown in any one of SEQ ID NOs: 48-55, and LC-CDR3 comprising the amino acid sequence shown in any one of SEQ ID NOs: NOs:56-72, or a variant of the light chain variable domain, wherein the LC-CDR sequence comprises a substitution of up to about 5 (e.g., 1, 2, 3, 4, or 5) amino acids. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:107. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:107 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:107 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:110.

[0230] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG4 constant region is provided, wherein the anti-FXIIa antibody comprises a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence shown in any one of SEQ ID NOs: 1-9, HC-CDR2 comprising the amino acid sequence shown in any one of SEQ ID NOs: 10-21, and HC-CDR3 comprising the amino acid sequence shown in any one of SEQ ID NOs: 22-33, or a variant of the heavy chain variable domain, wherein the HC-CDR sequence comprises up to about 5 (e.g., 1, 2, 3, 4 or 5) amino acid substitutions; and b) a light chain variable domain, the light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence shown in any one of SEQ ID NOs: 34-47, LC-CDR2 comprising the amino acid sequence shown in any one of SEQ ID NOs: 48-55, and LC-CDR3 comprising the amino acid sequence shown in any one of SEQ ID NOs: 50-57. NOs:56-72, or a variant of the light chain variable domain, wherein the LC-CDR sequence comprises a substitution of up to about 5 (e.g., 1, 2, 3, 4, or 5) amino acids. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:108. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:108 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:108 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:110.

[0231] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG1 constant region is provided, wherein the anti-FXIIa antibody comprises: a) a heavy chain variable domain comprising: HC-CDR1 comprising an amino acid sequence as shown in any one of SEQ ID NOs: 1-9, HC-CDR2 comprising an amino acid sequence as shown in any one of SEQ ID NOs: 10-21, and HC-CDR3 comprising an amino acid sequence as shown in any one of SEQ ID NOs: 22-33; and b) a light chain variable domain comprising: LC-CDR1 comprising an amino acid sequence as shown in any one of SEQ ID NOs: 34-47, LC-CDR2 comprising an amino acid sequence as shown in any one of SEQ ID NOs: 48-55, and LC-CDR3 comprising an amino acid sequence as shown in any one of SEQ ID NOs: 56-72. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110.

[0232] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG4 constant region is provided, wherein the anti-FXIIa antibody comprises: a) a heavy chain variable domain comprising: HC-CDR1 comprising an amino acid sequence as shown in any one of SEQ ID NOs: 1-9, HC-CDR2 comprising an amino acid sequence as shown in any one of SEQ ID NOs: 10-21, and HC-CDR3 comprising an amino acid sequence as shown in any one of SEQ ID NOs: 22-33; and b) a light chain variable domain comprising: LC-CDR1 comprising an amino acid sequence as shown in any one of SEQ ID NOs: 34-47, LC-CDR2 comprising an amino acid sequence as shown in any one of SEQ ID NOs: 48-55, and LC-CDR3 comprising an amino acid sequence as shown in any one of SEQ ID NOs: 56-72. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110.

[0233] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG1 constant region is provided, wherein the anti-FXIIa antibody comprises: a) a heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 10, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 22; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 34, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 48, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 56. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110.

[0234] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG1 constant region is provided, wherein the anti-FXIIa antibody comprises: a) a heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 11, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 23; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 35, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 49, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 57. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110.

[0235] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG1 constant region is provided, wherein the anti-FXIIa antibody comprises: a) a heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 2, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 12, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 24; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 36, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 50, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 58. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110.

[0236] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG1 constant region is provided, wherein the anti-FXIIa antibody comprises: a) a heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 3, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 13, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 25; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 37, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 51, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 59. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110.

[0237] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG1 constant region is provided, wherein the anti-FXIIa antibody comprises: a) a heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 4, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 14, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 26; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 37, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 51, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 60. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110.

[0238] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG1 constant region is provided, wherein the anti-FXIIa antibody comprises: a) a heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 3, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 13, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 25; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 37, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 51, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 61. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110.

[0239] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG1 constant region is provided, wherein the anti-FXIIa antibody comprises: a) a heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 2, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 12, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 24; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 38, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 50, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 62. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110.

[0240] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG1 constant region is provided, wherein the anti-FXIIa antibody comprises: a) a heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 3, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 13, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 25; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 39, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 52, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 63. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110.

[0241] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG1 constant region is provided, wherein the anti-FXIIa antibody comprises: a) a heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 10, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 27; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 40, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 53, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 64. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110.

[0242] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG1 constant region is provided, wherein the anti-FXIIa antibody comprises: a) a heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 5, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 15, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 28; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 41, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 50, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 65. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110.

[0243] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG1 constant region is provided, wherein the anti-FXIIa antibody comprises: a) a heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 6, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 16, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 29; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 42, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 54, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 66. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110.

[0244] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG1 constant region is provided, wherein the anti-FXIIa antibody comprises: a) a heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 6, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 17, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 30; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 43, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 50, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 67. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110.

[0245] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG1 constant region is provided, wherein the anti-FXIIa antibody comprises: a) a heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 5, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 15, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 28; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 44, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 50, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 68. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110.

[0246] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG1 constant region is provided, wherein the anti-FXIIa antibody comprises: a) a heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO:7, HC-CDR2 comprising the amino acid sequence of SEQ ID NO:18, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO:31; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO:45, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:55, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO:69. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:107. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110.

[0247] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG1 constant region is provided, wherein the anti-FXIIa antibody comprises: a) a heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 8, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 19, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 28; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 46, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 50, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 70. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110.

[0248] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG1 constant region is provided, wherein the anti-FXIIa antibody comprises: a) a heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 9, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 20, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 32; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 47, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 51, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 71. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110.

[0249] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG1 constant region is provided, wherein the anti-FXIIa antibody comprises: a) a heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 3, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 21, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 33; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 37, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 51, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 72. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110.

[0250] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG4 constant region is provided, wherein the anti-FXIIa antibody comprises: a) a heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 10, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 22; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 34, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 48, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 56. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110.

[0251] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG4 constant region is provided, wherein the anti-FXIIa antibody comprises: a) a heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 11, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 23; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 35, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 49, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 57. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110.

[0252] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG4 constant region is provided, wherein the anti-FXIIa antibody comprises: a) a heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 2, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 12, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 24; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 36, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 50, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 58. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110.

[0253] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG4 constant region is provided, wherein the anti-FXIIa antibody comprises: a) a heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 3, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 13, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 25; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 37, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 51, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 59. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110.

[0254] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG4 constant region is provided, wherein the anti-FXIIa antibody comprises: a) a heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 4, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 14, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 26; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 37, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 51, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 60. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110.

[0255] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG4 constant region is provided, wherein the anti-FXIIa antibody comprises: a) a heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 3, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 13, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 25; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 37, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 51, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 61. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110.

[0256] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG4 constant region is provided, wherein the anti-FXIIa antibody comprises: a) a heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 2, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 12, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 24; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 38, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 50, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 62. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110.

[0257] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG4 constant region is provided, wherein the anti-FXIIa antibody comprises: a) a heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 3, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 13, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 25; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 39, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 52, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 63. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110.

[0258] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG4 constant region is provided, wherein the anti-FXIIa antibody comprises: a) a heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 10, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 27; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 40, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 53, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 64. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110.

[0259] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG4 constant region is provided, wherein the anti-FXIIa antibody comprises: a) a heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 5, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 15, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 28; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 41, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 50, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 65. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110.

[0260] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG4 constant region is provided, wherein the anti-FXIIa antibody comprises: a) a heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 6, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 16, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 29; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 42, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 54, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 66. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110.

[0261] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG4 constant region is provided, wherein the anti-FXIIa antibody comprises: a) a heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 6, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 17, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 30; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 43, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 50, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 67. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110.

[0262] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG4 constant region is provided, wherein the anti-FXIIa antibody comprises: a) a heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 5, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 15, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 28; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 44, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 50, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 68. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110.

[0263] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG4 constant region is provided, wherein the anti-FXIIa antibody comprises: a) a heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO:7, HC-CDR2 comprising the amino acid sequence of SEQ ID NO:18, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO:31; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO:45, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:55, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO:69. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:108. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110.

[0264] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG4 constant region is provided, wherein the anti-FXIIa antibody comprises: a) a heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 8, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 19, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 28; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 46, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 50, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 70. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110.

[0265] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG4 constant region is provided, wherein the anti-FXIIa antibody comprises: a) a heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 9, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 20, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 32; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 47, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 51, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 71. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110.

[0266] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG4 constant region is provided, wherein the anti-FXIIa antibody comprises: a) a heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 3, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 21, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 33; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 37, LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 51, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 72. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110.

[0267] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG1 constant region is provided, wherein the anti-FXIIa antibody comprises: a heavy chain variable domain (V H ), the V H The invention comprises an amino acid sequence as shown in any one of SEQ ID NOs: 73-89 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with the amino acid sequence as shown in any one of SEQ ID NOs: 73-89; and a light chain variable domain (V L ), the V LComprising an amino acid sequence as shown in any one of SEQ ID NOs:90-106 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with the amino acid sequence as shown in any one of SEQ ID NOs:90-106. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:107. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:107 and the light chain constant region comprises or consists of the amino acid sequence

[0268] In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110.

[0269] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG2 constant region is provided, wherein the anti-FXIIa antibody comprises: a heavy chain variable domain (V H ), the V H The invention comprises an amino acid sequence as shown in any one of SEQ ID NOs: 73-89 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with the amino acid sequence as shown in any one of SEQ ID NOs: 73-89; and a light chain variable domain (V L ), the V L The invention relates to an IgG2 polypeptide comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 90-106 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with the amino acid sequence as set forth in any one of SEQ ID NOs: 90-106. In some embodiments, the IgG2 is a human IgG2. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110.

[0270] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG3 constant region is provided, wherein the anti-FXIIa antibody comprises: a heavy chain variable domain (V H), the V H The invention comprises an amino acid sequence as shown in any one of SEQ ID NOs: 73-89 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with the amino acid sequence as shown in any one of SEQ ID NOs: 73-89; and a light chain variable domain (V L ), the V L The invention relates to an IgG3 polypeptide comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 90-106 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with the amino acid sequence as set forth in any one of SEQ ID NOs: 90-106. In some embodiments, the IgG3 is a human IgG3. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110.

[0271] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG4 constant region is provided, wherein the anti-FXIIa antibody comprises: a heavy chain variable domain (V H ), the V H The invention comprises an amino acid sequence as shown in any one of SEQ ID NOs: 73-89 or a variant thereof, wherein the variant has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity with the amino acid sequence as shown in any one of SEQ ID NOs: 73-89; and a light chain variable domain (V L ), the V L In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110.

[0272] In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110.

[0273] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG1 constant region is provided, wherein the anti-FXIIa antibody comprises: a heavy chain variable domain (V H ), the V H Comprising the amino acid sequence shown in any one of SEQ ID NOs:73-89, and a light chain variable domain (V L ), the V L In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110.

[0274] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG4 constant region is provided, wherein the anti-FXIIa antibody comprises: a heavy chain variable domain (V H ), the V H Comprising the amino acid sequence shown in any one of SEQ ID NOs:73-89, and a light chain variable domain (V L ), the V LIn some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110.

[0275] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG1 constant region is provided, wherein the anti-FXIIa antibody comprises: V H , comprising the amino acid sequence of SEQ ID NO: 73 or a variant thereof, wherein the variant has at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 73; and V L , which comprises the amino acid sequence of SEQ ID NO:90 or a variant thereof, the variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO:90. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:107. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:110.

[0276] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG1 constant region is provided, wherein the anti-FXIIa antibody comprises: V H , comprising the amino acid sequence of SEQ ID NO: 74 or a variant thereof, wherein the variant has at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 74; and V L, which comprises the amino acid sequence of SEQ ID NO:91 or a variant thereof, the variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO:91. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:107. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:110.

[0277] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG1 constant region is provided, wherein the anti-FXIIa antibody comprises: V H , comprising the amino acid sequence of SEQ ID NO: 75 or a variant thereof, wherein the variant has at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 75; and V L , which comprises the amino acid sequence of SEQ ID NO:92 or a variant thereof, the variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO:92. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:107. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:110.

[0278] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG1 constant region is provided, wherein the anti-FXIIa antibody comprises: V H , comprising the amino acid sequence of SEQ ID NO: 76 or a variant thereof, wherein the variant has at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 76; and V L, which comprises the amino acid sequence of SEQ ID NO:93 or a variant thereof, the variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO:93. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:107. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:110.

[0279] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG1 constant region is provided, wherein the anti-FXIIa antibody comprises: V H , comprising the amino acid sequence of SEQ ID NO: 77 or a variant thereof, wherein the variant has at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 77; and V L , which comprises the amino acid sequence of SEQ ID NO:94 or a variant thereof, the variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO:94. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:107. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:110.

[0280] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG1 constant region is provided, wherein the anti-FXIIa antibody comprises: V H , comprising the amino acid sequence of SEQ ID NO: 78 or a variant thereof, wherein the variant has at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 78; and V L, which comprises the amino acid sequence of SEQ ID NO:95 or a variant thereof, the variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO:95. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:107. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:110.

[0281] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG1 constant region is provided, wherein the anti-FXIIa antibody comprises: V H , comprising the amino acid sequence of SEQ ID NO: 79 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 79; and V L , which comprises the amino acid sequence of SEQ ID NO:96 or a variant thereof, the variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO:96. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:107. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:110.

[0282] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG1 constant region is provided, wherein the anti-FXIIa antibody comprises: V H , comprising the amino acid sequence of SEQ ID NO: 80 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 80; and V L, which comprises the amino acid sequence of SEQ ID NO:97 or a variant thereof, the variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO:97. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:107. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:110.

[0283] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG1 constant region is provided, wherein the anti-FXIIa antibody comprises: V H , comprising the amino acid sequence of SEQ ID NO: 81 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 81; and V L , which comprises the amino acid sequence of SEQ ID NO:98 or a variant thereof, the variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO:98. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:107. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:110.

[0284] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG1 constant region is provided, wherein the anti-FXIIa antibody comprises: V H , comprising the amino acid sequence of SEQ ID NO: 82 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 82; and V L, which comprises the amino acid sequence of SEQ ID NO:99 or a variant thereof, the variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO:99. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:107. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:110.

[0285] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG1 constant region is provided, wherein the anti-FXIIa antibody comprises: V H , comprising the amino acid sequence of SEQ ID NO: 83 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 83; and V L , comprising the amino acid sequence of SEQ ID NO: 100 or a variant thereof having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 100. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence

[0286] SEQ ID NO: 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110.

[0287] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG1 constant region is provided, wherein the anti-FXIIa antibody comprises: V H, comprising the amino acid sequence of SEQ ID NO: 84 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 84; and V L , comprising the amino acid sequence of SEQ ID NO: 101 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 101. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence

[0288] SEQ ID NO: 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110.

[0289] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG1 constant region is provided, wherein the anti-FXIIa antibody comprises: V H , comprising the amino acid sequence of SEQ ID NO: 85 or a variant thereof, wherein the variant has at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 85; and V L , comprising the amino acid sequence of SEQ ID NO: 102 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 102. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence

[0290] SEQ ID NO: 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110.

[0291] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG1 constant region is provided, wherein the anti-FXIIa antibody comprises: V H , comprising the amino acid sequence of SEQ ID NO: 86 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 86; and V L , which comprises the amino acid sequence of SEQ ID NO: 103 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 103. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence

[0292] SEQ ID NO: 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110.

[0293] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG1 constant region is provided, wherein the anti-FXIIa antibody comprises: V H , comprising the amino acid sequence of SEQ ID NO: 87 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 87; and V L , comprising the amino acid sequence of SEQ ID NO: 104 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 104. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence

[0294] SEQ ID NO: 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110.

[0295] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG1 constant region is provided, wherein the anti-FXIIa antibody comprises: V H , comprising the amino acid sequence of SEQ ID NO: 88 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 88; and V L , comprising the amino acid sequence of SEQ ID NO: 105 or a variant thereof having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 105. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence

[0296] SEQ ID NO: 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110.

[0297] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG1 constant region is provided, wherein the anti-FXIIa antibody comprises: V H , comprising the amino acid sequence of SEQ ID NO: 89 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 89; and V L, comprising the amino acid sequence of SEQ ID NO: 106 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 106. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence

[0298] SEQ ID NO: 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 107 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110.

[0299] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG4 constant region is provided, wherein the anti-FXIIa antibody comprises: V H , comprising the amino acid sequence of SEQ ID NO: 73 or a variant thereof, wherein the variant has at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 73; and V L , which comprises the amino acid sequence of SEQ ID NO:90 or a variant thereof having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO:90. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:108. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:110.

[0300] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG4 constant region is provided, wherein the anti-FXIIa antibody comprises: V H, comprising the amino acid sequence of SEQ ID NO: 74 or a variant thereof, wherein the variant has at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 74; and V L , which comprises the amino acid sequence of SEQ ID NO:91 or a variant thereof, the variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO:91. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:108. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:110.

[0301] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG4 constant region is provided, wherein the anti-FXIIa antibody comprises: V H , comprising the amino acid sequence of SEQ ID NO: 75 or a variant thereof, wherein the variant has at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 75; and V L , which comprises the amino acid sequence of SEQ ID NO:92 or a variant thereof, the variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO:92. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:108. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:110.

[0302] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG4 constant region is provided, wherein the anti-FXIIa antibody comprises: V H, comprising the amino acid sequence of SEQ ID NO: 76 or a variant thereof, wherein the variant has at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 76; and V L , which comprises the amino acid sequence of SEQ ID NO:93 or a variant thereof, the variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO:93. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:108. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:110.

[0303] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG4 constant region is provided, wherein the anti-FXIIa antibody comprises: V H , comprising the amino acid sequence of SEQ ID NO: 77 or a variant thereof, wherein the variant has at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 77; and V L , which comprises the amino acid sequence of SEQ ID NO:94 or a variant thereof, the variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO:94. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:108. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:110.

[0304] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG4 constant region is provided, wherein the anti-FXIIa antibody comprises: V H, comprising the amino acid sequence of SEQ ID NO: 78 or a variant thereof, wherein the variant has at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 78; and V L , which comprises the amino acid sequence of SEQ ID NO:95 or a variant thereof, the variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO:95. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:108. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:110.

[0305] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG4 constant region is provided, wherein the anti-FXIIa antibody comprises: V H , comprising the amino acid sequence of SEQ ID NO: 79 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 79; and V L , which comprises the amino acid sequence of SEQ ID NO:96 or a variant thereof, the variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO:96. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:108. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:110.

[0306] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG4 constant region is provided, wherein the anti-FXIIa antibody comprises: V H, comprising the amino acid sequence of SEQ ID NO: 80 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 80; and V L , which comprises the amino acid sequence of SEQ ID NO:97 or a variant thereof, the variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO:97. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:108. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:110.

[0307] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG4 constant region is provided, wherein the anti-FXIIa antibody comprises: V H , comprising the amino acid sequence of SEQ ID NO: 81 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 81; and V L , which comprises the amino acid sequence of SEQ ID NO:98 or a variant thereof, the variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO:98. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:108. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:110.

[0308] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG4 constant region is provided, wherein the anti-FXIIa antibody comprises: V H, comprising the amino acid sequence of SEQ ID NO: 82 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 82; and V L , which comprises the amino acid sequence of SEQ ID NO:99 or a variant thereof, the variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO:99. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:108. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:110.

[0309] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG4 constant region is provided, wherein the anti-FXIIa antibody comprises: V H , comprising the amino acid sequence of SEQ ID NO: 83 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 83; and V L , which comprises the amino acid sequence of SEQ ID NO: 100 or a variant thereof, the variant having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 100. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence

[0310] SEQ ID NO: 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110.

[0311] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG4 constant region is provided, wherein the anti-FXIIa antibody comprises: V H , comprising the amino acid sequence of SEQ ID NO: 84 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 84; and V L , comprising the amino acid sequence of SEQ ID NO: 101 or a variant thereof having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 101. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence

[0312] SEQ ID NO: 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110.

[0313] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG4 constant region is provided, wherein the anti-FXIIa antibody comprises: V H , comprising the amino acid sequence of SEQ ID NO: 85 or a variant thereof, wherein the variant has at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 85; and V L , which comprises the amino acid sequence of SEQ ID NO: 102 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 102. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence

[0314] SEQ ID NO: 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110.

[0315] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG4 constant region is provided, wherein the anti-FXIIa antibody comprises: V H , comprising the amino acid sequence of SEQ ID NO: 86 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 86; and V L , which comprises the amino acid sequence of SEQ ID NO: 103 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 103. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence

[0316] SEQ ID NO: 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110.

[0317] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG4 constant region is provided, wherein the anti-FXIIa antibody comprises: V H , comprising the amino acid sequence of SEQ ID NO: 87 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 87; and V L, comprising the amino acid sequence of SEQ ID NO: 104 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 104. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence

[0318] SEQ ID NO: 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110.

[0319] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG4 constant region is provided, wherein the anti-FXIIa antibody comprises: V H , comprising the amino acid sequence of SEQ ID NO: 88 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 88; and V L , which comprises the amino acid sequence of SEQ ID NO: 105 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 105. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence

[0320] SEQ ID NO: 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110.

[0321] In some embodiments, a full-length anti-FXIIa antibody comprising an IgG4 constant region is provided, wherein the anti-FXIIa antibody comprises: V H, comprising the amino acid sequence of SEQ ID NO: 89 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 89; and V L , which comprises the amino acid sequence of SEQ ID NO: 106 or a variant thereof, wherein the variant has at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 106. In some embodiments, the IgG4 is a human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence

[0322] SEQ ID NO: 110. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 109. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 108 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 110.

[0323] Binding affinity

[0324] Binding affinity is expressed as Kd, Koff, Kon or Ka. As used herein, the term Koff refers to the rate constant for the dissociation of an antibody from an antigen / antibody complex, measured by a kinetic selection apparatus. The term Kon refers to the association rate constant for the binding of an antibody to an antigen to form an antigen / antibody complex. The equilibrium dissociation constant Kd used herein refers to the dissociation constant for a specific antibody-antigen interaction, and refers to the antigen concentration required in a solution of antibody molecules for the antigen to occupy half of all antibody binding sites and to reach equilibrium, which is equal to Koff / Kon. The determination of Kd assumes that all binding molecules are in solution. In the case where the antibody is attached to the cell wall, such as in a yeast expression system, the corresponding equilibrium dissociation rate constant is expressed as EC 50 It is expressed as , which is a good approximation of Kd. The affinity binding constant Ka is the reciprocal of the dissociation constant Kd.

[0325] The dissociation constant (Kd) can be used as an indicator of the affinity of the reactive antibody moiety for the antigen. For example, simple analysis can be performed by the Scatchard method using antibodies labeled with various markers and a Biacore instrument (manufactured by Amersham Biosciences) to analyze the interaction between biomolecules by surface plasmon resonance according to the user manual or the accompanying kit. The Kd values ​​obtained using these methods are expressed in units of M. An antibody that specifically binds to a target may have, for example, ≤10-7 M, ≤10 -8 M, ≤10 -9 M, ≤ 10 -10 M, ≤10 -11 M, ≤10 -12 M or ≤10 -13 Kd value of M.

[0326] The binding specificity of the antibody can be experimentally determined by methods known in the art, including, but not limited to, Western blots, ELISA-, RIA-, ECL-, IRMA-, EIA-, BIAcore assays, and peptide scanning.

[0327] In some embodiments, the anti-FXIIa antibody specifically binds to the FXIIa target with a Kd value of 10 -7 M to 10 -13 M (e.g. 10 -7 M to 10 -13 M, 10 -8 M to 10 -13 M, 10 -9 M to 10 -13 M or 10 -10 M to 10 -12 M). Therefore, in some embodiments, the Kd value of the binding between the anti-FXIIa antibody and FXIIa is 10 -7 M to 10 -13 M, 1×10 -7 M to 5×10 -13 M, 10 -7 M to 10 -12 M, 10 -7 M to 10 -11 M, 10 -7 M to 10 -10 M, 10 -7 M to 10 -9 M, 10 -8 M to 10 -13 M, 1×10 -8 M to 5×10 -13 M, 10 -8 M to 10 - 12 M, 10 -8 M to 10 -11 M, 10 -8 M to 10 -10 M, 10 -8 M to 10 -9 M, 5×10 -9 M to 1×10 -13 M, 5×10 -9M to 1×10 -12 M, 5×10 -9 M to 1×10 -11 M, 5×10 -9 M to 1×10 -10 M, 10 -9 M to 10 -13 M, 10 -9 M to 10 -12 M, 10 -9 M to 10 -11 M, 10 -9 M to 10 -10 M, 5×10 -10 M to 1×10 -13 M, 5×10 -10 M to 1×10 -12 M, 5×10 -10 M to 1×10 -11 M, 10 -10 M to 10 - 13 M, 1×10 -10 M to 5×10 -13 M, 1×10 -10 M to 1×10 -12 M, 1×10 -10 M to 5×10 -12 M, 1×10 -10 M to 1×10 - 11 M, 10 -11 M to 10 -13 M, 1×10 -11 M to 5×10 -13 M, 10 -11 M to 10 -12 M, 10 -12 M to 10 -13 M. In some embodiments, the Kd value of the binding between the anti-FXIIa antibody and FXIIa is 10 -7 M to 10 -13 M.

[0328] In some embodiments, the Kd value of the binding between the anti-FXIIa antibody and the non-target is higher than the Kd value of the anti-FXIIa antibody and the target, and in some embodiments cited herein, the binding affinity of the anti-FXIIa antibody to the target (e.g., FXIIa) is higher than the binding affinity of the anti-FXIIa antibody to the non-target. In some embodiments, the non-target refers to an antigen other than FXIIa. In some embodiments, the Kd value of the binding between the anti-FXIIa antibody (for FXIIa) and the non-FXIIa target differs by at least 10 times, such as 10-100 times, 100-1000 times, 103 -10 4 times, 10 4 -10 5 times, 10 5 -10 6 times, 10 6 -10 7 times, 10 7 -10 8 times, 10 8 -10 9 times, 10 9 -10 10 times, 10 10 -10 11 times, 10 11 -10 12 times.

[0329] In some embodiments, the anti-FXIIa antibody has a Kd value of 10 for binding to a non-target -1 M to 10 -6 M (e.g. 10 - 1 M to 10 -6 M, 10 -1 M to 10 -5 M, 10 -2 M to 10 -4 M). In some embodiments, the non-target is an antigen other than FXIIa. Thus, in some embodiments, the Kd value of the binding between the anti-FXIIa antibody and the non-FXIIa target is 10 -1 M to 10 -6 M, 1×10 -1 M to 5×10 -6 M, 10 -1 M to 10 -5 M, 1×10 -1 M to 5×10 -5 M, 10 -1 M to 10 -4 M, 1×10 -1 M to 5×10 -4 M, 10 -1 M to 10 -3 M, 1×10 -1 M to 5×10 -3 M, 10 -1 M to 10 -2 M, 10 -2 M to 10 -6 M, 1×10 -2 M to 5×10 -6 M, 10 -2 M to 10 - 5M, 1×10 -2 M to 5×10 -5 M, 10 -2 M to 10 -4 M, 1×10 -2 M to 5×10 -4 M, 10 -2 M to 10 -3 M, 10 -3 M to 10 -6 M, 1×10 -3 M to 5×10 -6 M, 10 -3 M to 10 -5 M, 1×10 -3 M to 5×10 -5 M, 10 -3 M to 10 -4 M, 10 -4 M to 10 -6 M, 1×10 -4 M to 5×10 -6 M, 10 -4 M to 10 -5 M, 10 -5 M to 10 -6 M.

[0330] In some embodiments, when it is mentioned that the anti-FXIIa antibody specifically recognizes the FXIIa target with high binding affinity and binds to the non-target with low binding affinity, the Kd value of the anti-FXIIa antibody binding to the FXIIa target is 10 -7 M to 10 - 13 M (e.g. 10 -7 M to 10 -13 M, 10 -8 M to 10 -13 M, 10 -9 M to 10 -13 M, 10 -10 M to 10 -12 M), and the Kd value for binding to non-target is 10 -1 M to 10 -6 M (e.g. 10 -1 M to 10 -6 M, 10 -1 M to 10 -5 M, 10 -2 M to 10 -4 M).

[0331] In some embodiments, when it is mentioned that the anti-FXIIa antibody specifically recognizes FXIIa, the binding affinity of the anti-FXIIa antibody is compared with the binding affinity of a control anti-FXIIa antibody (e.g., CSL312). In some embodiments, the Kd value of the binding between the control anti-FXIIa antibody and FXIIa can be at least 2 times the Kd value of the binding between the anti-FXIIa antibody described in the present application and FXIIa, such as 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, 10-100 times, 100-1000 times, 1 ... 3 -10 4 times.

[0332] Nucleic Acids

[0333] Nucleic acid molecules encoding anti-FXIIa antibodies are also contemplated. In some embodiments, a nucleic acid (or a group of nucleic acids) encoding a full-length anti-FXIIa antibody is provided, including any full-length anti-FXIIa antibody described herein. In some embodiments, the nucleic acid (or a group of nucleic acids) of the anti-FXIIa antibody described herein may also include a nucleic acid sequence encoding a polypeptide tag (e.g., a protein purification tag, a His tag, an HA tag).

[0334] Also contemplated herein are isolated host cells comprising an anti-FXIIa antibody, isolated nucleic acids encoding an anti-FXIIa antibody polypeptide component, or vectors comprising a nucleic acid encoding an anti-FXIIa antibody polypeptide component as described herein.

[0335] The present application also includes variants of these nucleic acid sequences. For example, the variant includes a nucleotide sequence that hybridizes with the nucleic acid sequence encoding the anti-FXIIa antibody of the present application under at least moderately stringent hybridization conditions.

[0336] The present application also provides a vector into which the nucleic acid sequence of the present application can be inserted.

[0337] In brief, a natural or synthetic nucleic acid encoding an anti-FXIIa antibody is inserted into a suitable expression vector such that the nucleic acid is operably linked to 5' and 3' regulatory elements, such as a promoter (e.g., a lymphocyte-specific promoter) and a 3' untranslated region (UTR), and an anti-FXIIa antibody (e.g., a full-length anti-FXIIa antibody) can be expressed. The vector can be suitable for replication and integration in eukaryotic host cells. Typical cloning and expression vectors contain transcription and translation terminators, initiation sequences, and promoters that regulate the expression of the target nucleic acid sequence.

[0338] The nucleic acids described herein can also be used for nucleic acid immunization and gene therapy by using standard gene delivery protocols. Nucleic acid delivery methods are known in the art. For example, see US Pat. Nos. 5,399,346, 5,580,859, 5,589,466, which are incorporated herein by reference in their entirety. In some embodiments, the present application also provides gene therapy vectors.

[0339] Nucleic acids can be cloned into many types of vectors. For example, nucleic acids can be cloned into vectors including, but not limited to, plasmids, phagemids, phage derivatives, animal viruses, and cosmids. Vectors of particular interest include expression vectors, replication vectors, probe generation vectors, and sequencing vectors.

[0340] In addition, the expression vector can be provided to the cell in the form of a viral vector. Viral vector technology is well known in the art and is described in, for example, Green and Sambrook (2013, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, New York), and other virology or molecular biology manuals. The virus that can be used as a vector includes, but is not limited to, retrovirus, adenovirus, adeno-associated virus, herpes virus and slow virus. Generally, suitable vectors include a replication origin, a promoter sequence, a convenient restriction endonuclease site and one or more selection markers that work in at least one organism (see, for example, WO 01 / 96584; WO 01 / 29058; and US Pat. No. 6,326,193).

[0341] Many virus-based systems have been developed for transferring genes into mammalian cells. For example, retroviruses provide a convenient platform for gene delivery systems. The selected gene can be inserted into a vector and packaged in retroviral particles using techniques known in the art. The recombinant virus is then isolated and delivered to the cells of the subject in vivo or in vitro. Many retroviral systems are known in the art. In some embodiments, adenoviral vectors are used. Many adenoviral vectors are known in the art. In some embodiments, lentiviral vectors are used. Vectors derived from retroviruses, such as lentiviruses, are suitable tools for achieving long-term gene transfer because they allow long-term stable integration of transgenes and reproduction in daughter cells. Lentiviral vectors have additional advantages over retroviruses derived from tumors, such as mouse leukemia viruses, because they can transduce non-dividing cells, such as hepatocytes. At the same time, it also has the additional advantage of low immunogenicity.

[0342] Other promoter elements, such as enhancers, regulate the frequency of transcription initiation. They are usually located 30-110 bp upstream of the start site, although recently it has been discovered that many promoters also contain functional elements downstream of the start site. The spacing between promoter elements is usually flexible, so that the promoter function is maintained when the elements are interchanged or moved relative to each other. In the thymidine kinase (tk) promoter, the activity begins to decline only when the spacing between promoter elements increases to 50 bp.

[0343] An example of a suitable promoter is the immediate early cytomegalovirus (CMV) promoter sequence. This promoter sequence is a very strong constitutive promoter sequence that can drive any polynucleotide sequence operably connected thereto to express at a high level. Another example of a suitable promoter is the elongation factor 1α (EF-1α) promoter. However, other constitutive promoters may also be used, including but not limited to the simian virus 40 (SV40) early promoter, mouse mammary tumor virus (MMTV), human immunodeficiency virus long terminal repeat (HIV-LTR) promoter, MoMuLV promoter, avian leukosis virus promoter, Epstein-Barr virus immediate early promoter, Rous sarcoma virus promoter, and human gene promoters, including but not limited to actin promoter, myosin promoter, hemoglobin promoter, and creatine kinase promoter. In addition, the present application should not be limited to using only constitutive promoters, and inducible promoters are also considered in the present application. The use of an inducible promoter provides a molecular switch that turns on the expression of a polynucleotide sequence to which it is operably linked when such expression is desired and turns off expression when it is not desired. Inducible promoters include, but are not limited to, metallothionein promoters, glucocorticoid promoters, progesterone promoters, and tetracycline promoters.

[0344] In some embodiments, expression of the anti-FXIIa antibody is inducible. In some embodiments, the nucleic acid sequence encoding the anti-FXIIa antibody is operably linked to an inducible promoter, including any of the inducible promoters described herein.

[0345] Inducible promoter

[0346] The use of an inducible promoter provides a molecular switch that turns on the expression of a polynucleotide sequence operably linked thereto when expression is desired, and turns off expression when expression is not desired. Exemplary inducible promoters suitable for use in eukaryotic cells include, but are not limited to, hormone-regulated elements (e.g., see Mader, S. and White, JH (1993) Proc. Natl. Acad. Sci. USA 90:5603-5607), synthetic ligand-regulated elements (see Spencer, DM et al (1993) Science 262:1019-1024), and ionizing radiation-regulated elements (see Manome, Y. et al (1993) Biochemistry 32:10607-10613; Datta, R. et al (1992) Proc. Natl. Acad. Sci. USA 89:1014-10153). Other exemplary inducible promoters suitable for use in in vivo or in vitro mammalian systems are described in Gingrich et al. (1998) Annual Rev. Neurosci 21: 377-405. In some embodiments, the inducible promoter system used to express anti-FXIIa antibodies is the Tet system. In some embodiments, the inducible promoter system used to express anti-FXIIa antibodies is the E. coli lac repression system.

[0347] An exemplary inducible promoter system used in the present application is the Tet system. The system is based on the Tet system described by Gossen et al. (1993). In an exemplary embodiment, the target polynucleotide is controlled by a promoter comprising one or more Tet operator (TetO) sites. In the inactive state, the Tet repressor (TetR) binds to the TetO site and inhibits transcription of the promoter. In the activated state, for example, in the presence of an inducer such as tetracycline (Tc), anhydrotetracycline, doxycycline (Dox) or its active analogs, the inducer releases TetR from TetO, thereby causing transcription to occur. Doxycycline is a member of the tetracycline antibiotic family, and its chemical name is 1-dimethylamino-2,4a,5,7-pentahydroxy-11-methyl-4,6-dioxy-1,4a,11,11a,12,12a-hexahydrotetraene-3-carboxamide.

[0348] In one embodiment, TetR is codon optimized for expression in mammalian cells, such as mice or human cells. Due to the degeneracy of the genetic code, most amino acids are encoded by more than one codon, so that the sequence of a given nucleic acid has a large number of variants, and the amino acid sequence encoded by it does not change at all. However, many organisms have differences in codon usage, also known as "codon preference" (i.e., the preference for using specific codons for a given amino acid). Codon preference is generally related to the presence of a dominant tRNA species for a specific codon, which in turn improves the efficiency of mRNA translation. Therefore, coding sequences derived from specific species (e.g., prokaryotes) can be customized by codon optimization to improve their expression in different species (e.g., eukaryotes).

[0349] Other specific variants of the Tet system include the following "Tet-Off" and "Tet-On" systems. In the Tet-off system, transcription is inactivated in the presence of Tc or Dox. In this system, a tetracycline-regulated transcription activator protein (tTA), which is composed of a fusion of TetR and the strong transcription activation domain of herpes simplex virus VP16, regulates the expression of the target nucleic acid under the transcriptional control of a tetracycline-responsive promoter element (TRE). The TRE element consists of a fusion of the TetO sequence in series with a promoter (usually a minimal promoter sequence derived from the immediate early promoter of human cytomegalovirus). In the absence of Tc or Dox, tTA binds to TRE and activates transcription of the target gene. In the presence of Tc or Dox, tTA cannot bind to TRE and the target gene cannot be expressed.

[0350] In contrast, in the Tet-On system, transcription is activated in the presence of Tc or Dox. The Tet-On system is based on the reverse tetracycline-regulated transcription activator rtTA. Like tTA, rtTA is a fusion protein consisting of the TetR repressor and the VP16 transcription activation domain. However, changes in four amino acids in the DNA binding region of TetR alter the binding properties of rtTA, allowing it to only recognize the tetO sequence on the target transgene TRE in the presence of Dox. Therefore, in the Tet-On system, rtTA can only activate the transcription of the target gene regulated by the TRE in the presence of Dox.

[0351] Another inducible promoter system is the lac repressor system of Escherichia coli (see Brown et al., Cell 49: 603-612 (1987)). The lac repressor system functions by regulating the transcription of a target polynucleotide operably linked to a promoter comprising a lac operator (lacO). The lac repressor (lacR) binds to LacO, thereby preventing transcription of the target polynucleotide. Expression of the target polynucleotide is induced by a suitable inducer, for example, isopropyl-β-D-thiogalactopyranoside (IPTG).

[0352] In order to evaluate the expression of polypeptide or part thereof, the expression vector to be introduced into the cell may also contain a selectable marker gene or a reporter gene or both, so as to identify and select expressing cells from a cell population transfected or infected by a viral vector. In other aspects, the selectable marker may be carried on a separate DNA fragment and used in a co-transfection experiment. Either the selectable marker gene or the reporter gene may be flanked by a suitable regulatory sequence to enable expression in the host cell. Useful selectable markers include, for example, antibiotic resistance genes, such as neo and similar genes.

[0353] Reporter genes can be used to identify potential transfected cells and evaluate the function of regulatory sequences. Generally, reporter genes are genes that are not present in or expressed by receptor organisms or tissues, and encode a polypeptide whose expression is expressed as some easily detectable characteristics, such as enzyme activity. After DNA is introduced into the receptor cells, the expression of the reporter gene is detected at the appropriate time. Suitable reporter genes may include genes encoding luciferase, beta-galactosidase, chloramphenicol acetyltransferase, secreted alkaline phosphatase or green fluorescent protein (see, Ui-Tel et al., 2000 FEBS Letters 479: 79-82). Suitable expression systems are well known and can be prepared by known techniques or obtained commercially. Generally, the construct of the minimum 5' flanking region that can show the highest expression level of the reporter gene is identified as a promoter. Such promoter regions can be connected to reporter genes and used to assess the ability of certain substances in regulating promoter-driven transcription.

[0354] In some embodiments, nucleic acids encoding any of the full-length anti-FXIIa antibodies described herein are provided. In some embodiments, the nucleic acid includes one or more nucleic acid sequences encoding full-length anti-FXIIa antibody heavy chains and light chains. In some embodiments, each of the one or more nucleic acid sequences is contained in a separate vector. In some embodiments, at least some nucleic acid sequences are contained in the same vector. In some embodiments, all nucleic acid sequences are contained in the same vector. The vector can be selected from, for example, mammalian expression vectors and viral vectors (such as vectors derived from retroviruses, adenoviruses, adeno-associated viruses, herpes viruses, and lentiviruses).

[0355] Methods for introducing genes into cells and expressing them are known in the art. In the context of expression vectors, the vectors can be easily introduced into host cells, such as mammalian cells, bacteria, yeast or insect cells, by any method in the art. For example, the expression vector can be introduced into the host cell by physical, chemical or biological methods.

[0356] Physical methods for introducing polynucleotides into host cells include calcium phosphate precipitation, liposome transfection, biolistic methods, microinjection, electroporation, and the like. Methods for preparing cells containing vectors and / or exogenous nucleic acids are well known in the art. See, for example, Green and Sambrook (2013, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, New York). In some embodiments, polynucleotides are introduced into host cells by calcium phosphate transfection.

[0357] Biological methods for introducing target polynucleotides into host cells include the use of DNA and RNA vectors. Viral vectors, particularly retroviral vectors, have become the most widely used methods for inserting genes into mammalian cells, such as human cells. Other viral vectors can be derived from lentiviruses, poxviruses, herpes simplex virus type 1, adenoviruses, and adeno-associated viruses, etc. See, for example, US Pat. Nos. 5,350,674 and 5,585,362.

[0358] Chemical methods for introducing polynucleotides into host cells include colloidal dispersion systems, such as polymer complexes, nanocapsules, microspheres, magnetic beads, and lipid-based systems, including oil-in-water emulsions, micelles, mixed micelles, and liposomes. An exemplary colloidal system used as a delivery vehicle in vivo and in vitro is a liposome (e.g., an artificial membrane vesicle).

[0359] In the case of using a non-viral delivery system, an exemplary delivery vehicle is a liposome. It is contemplated that a lipid formulation is used to import nucleic acid into a host cell (in vitro, in vitro or in vivo). On the other hand, the nucleic acid can be combined with a lipid. Nucleic acids combined with lipids can be wrapped into the aqueous interior of the liposome, dispersed in the lipid bilayer of the liposome, connected to the liposome by a linker molecule combined with the liposome and the oligonucleotide, embedded in the liposome, forming a complex with the liposome, dispersed in a solution containing lipids, mixed with lipids, combined with lipids, suspended in lipids, contained in micelles or mixed with micelles, or otherwise combined with lipids. The compositions related to lipids, lipid / DNA or lipid / expression vectors are not limited to any particular structure in solution. For example, they may exist in a bilayer structure, in micelles or in a "collapsed" structure. They can also be simply dispersed in a solution, possibly forming aggregates of uneven size or shape. Lipids are fatty substances, which can be naturally occurring or synthetic lipids. For example, lipids include fat droplets naturally present in the cytoplasm, as well as a class of compounds containing long-chain aliphatic hydrocarbons and their derivatives, such as fatty acids, alcohols, amines, amino alcohols, and aldehydes.

[0360] Regardless of the method used to introduce exogenous nucleic acid into the host cell or otherwise expose the cell to the inhibitor of the present application, a variety of experiments can be performed to confirm that the recombinant DNA sequence is present in the host cell. Such experiments include, for example, "molecular biology" experiments well known to those skilled in the art. For example, Southern and Northern blotting, RT-PCR and PCR; "biochemical" experiments, such as detecting the presence or absence of a particular polypeptide, such as by immunological methods (ELISAs and Western blots) or by the experiments described herein, are all within the scope of the present application.

[0361] Preparation of anti-FXIIa antibody

[0362] In some embodiments, the anti-FXIIa antibody is a monoclonal antibody or is derived from a monoclonal antibody. In some embodiments, the anti-FXIIa antibody comprises a V from a monoclonal antibody. H and V L , or a variant thereof. In some embodiments, the anti-FXIIa antibody further comprises a CH1 and CL region from a monoclonal antibody, or a variant thereof. Monoclonal antibodies can be prepared using methods known in the art, such as hybridoma cell methods, phage display methods, or using recombinant DNA methods. In addition, exemplary phage display methods are described herein and in the following examples.

[0363] In the hybridoma method, an immunizing agent is usually used to immunize hamsters, mice or other suitable host animals to induce lymphocytes that produce or are capable of producing antibodies that specifically bind to the immunizing agent. Alternatively, lymphocytes can be immunized in vitro. The immunizing agent may include a polypeptide or fusion protein of the target protein. Usually, if human cells are needed, peripheral blood lymphocytes (PBLs) are used, and if non-human mammalian cells are needed, spleen cells or lymph node cells are used. Lymphocytes are fused with immortal cell lines using an appropriate fusion agent, such as polyethylene glycol, to form hybridoma cells. Immortal cell lines are usually transformed mammalian cells, especially myeloma cells of rodents, bovines and humans. Rat or mouse myeloma cell lines are usually used. Hybridoma cells can be cultured in a suitable culture medium, and the culture medium preferably contains one or more substances that inhibit the growth or survival of unfused immortal cells. For example, if the parental cells lack the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT or HPRT), the hybridoma cell culture medium typically includes hypoxanthine, aminopterin, and thymidine (HAT medium), which prevents the growth of HGPRT-deficient cells.

[0364] In some embodiments, the immortalized cell line is effectively fused, and the antibody is stably expressed at a high level by the selected antibody production cells, and is sensitive to certain culture media, such as HAT culture media. In some embodiments, the immortalized cell line is a mouse myeloma cell line, which can be obtained from, for example, the Salk Cell Collection in San Diego, California and the American Type Culture Collection in Manassas, Virginia. Human myeloma and mouse-human hybrid myeloma cell lines are also described for the preparation of human monoclonal antibodies.

[0365] The presence of monoclonal antibodies against the polypeptide in the culture medium of the hybridoma cells can then be determined. The binding specificity of the monoclonal antibodies produced by the hybridoma cells can be determined by immunoprecipitation or in vitro binding experiments, such as radioimmunoassay (RIA) or enzyme-linked immunosorbent assay (ELISA). Such techniques or analytical methods are known in the art. The binding affinity of the monoclonal antibodies can be determined by, for example, Scatchard analysis as described in Munson and Pollard, Anal. Biochem., 107:220 (1980).

[0366] After identifying the desired hybridoma cells, the target clones can be subcloned by limiting dilution and cultured by standard methods. Suitable culture media for this purpose include, for example, modified Eagle medium (DMEM) and RPMI-1640 culture media. Alternatively, hybridoma cells can be grown in mammals in the form of ascites.

[0367] The monoclonal antibodies secreted by the subclones can be isolated or purified from the culture medium or ascites fluid by conventional immunoglobulin purification procedures, such as protein A-Sepharose, hydroxylapatite chromatography, gel electrophoresis, dialysis, or affinity chromatography.

[0368] In some embodiments, according to any anti-FXIIa antibody described herein, the anti-FXIIa antibody comprises a sequence of a clone selected from an antibody library (e.g., a phage library displaying scFv or Fab fragments). The clone can be identified by a method for screening a combinatorial library of antibody fragments having the desired activity. For example, a variety of methods are known in the art for generating phage display libraries and screening these libraries to obtain antibodies with desired binding properties. These methods are reviewed, for example, in Hoogenboom et al., Methods in Molecular Biology 178:1-37 (O'Brien et al., ed., Human Press, Totowa, NJ, 2001), and in, for example, McCafferty et al., Nature 348:552-554; Clackson et al., Nature 352:624-628 (1991); Marks et al., J. Mol. Biol. 222:581-597 (1992); Marks and Bradbury, Methods in Molecular Biology 248:161-175 (Lo, ed., Human Press, Totowa, NJ, 2003); Sidhu et al., J. Mol. Biol. 338(2):299-310 (2004); Lee et al., Nature 349:551-554 (1991); al., J. Mol. Biol. 340(5):1073-1093 (2004); Fellouse, Proc. Natl. Acad. Sci. USA 101(34):12467-12472 (2004); and Lee et al., J. Immunol. Methods 284(1-2):119-132 (2004).

[0369] In some phage display methods, V H and V LAll components of the gene are randomly recombined in a phage library, and then phages that can bind to the antigen are screened, as described in Winter et al., Ann. Rev. Immunol., 12: 433-455 (1994). Phages usually display antibody fragments in the form of scFv fragments or Fab fragments. Library phages of immune origin provide high-affinity antibodies against immunogens without the need to construct hybridoma cells. Alternatively, natural libraries (e.g., from humans) can be cloned to provide a single source of antibodies against a variety of non-self antigens and self antigens without any immunization, as described in Griffiths et al., EMBO J, 12: 725-734 (1993). Finally, natural libraries can also be prepared by cloning non-rearranged V-gene fragments from stem cells and using PCR primers containing random sequences to encode CDR3 hypervariable regions and complete rearrangement in vitro, as described in Hoogenboom and Winter, J. Mol. Biol., 227: 381-388 (1992). Patent publications describing human antibody phage libraries include, for example, US Pat. No. 5,750,373 and US Patent Publication Nos. 2005 / 0079574, 2005 / 0119455, 2005 / 0266000, 2007 / 0117126, 2007 / 0160598, 2007 / 0237764, 2007 / 0292936 and 2009 / 0002360.

[0370] The anti-FXIIa antibody is prepared by screening the anti-FXIIa antibody portion in the library by phage display. The library can be a human scFv phage display library with at least 1×10 9 (For example, at least 1×10 9 , 2.5×10 9 , 5×10 9 , 7.5×10 9 , 1×10 10 , 2.5×10 10 , 5×10 10 , 7.5×10 10 or 1×10 11) kinds of diverse unique human antibody fragments. In certain embodiments, the library is a human natural library, constructed by DNA extracted from PMBCs and spleen of healthy subjects, comprising all heavy and light chain subfamilies. In certain embodiments, the library is a human natural library, constructed by DNA extracted from PMBCs isolated from various disease patients, such as patients with autoimmune diseases, cancer patients and patients with infectious diseases. In certain embodiments, the library is a semisynthetic human library, wherein the heavy chain CDR3 is completely random, and all amino acids (except cysteine) are present in any given position with the same probability. (See, for example, Hoet, RMetal., Nat.Biotechnol.23 (3): 344-348, 2005). In certain embodiments, the heavy chain CDR3 length of the semisynthetic human library is between 5 and 24 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24) amino acids. In some embodiments, the library is a fully synthetic phage display library. In some embodiments, the library is a non-human phage display library.

[0371] Phage clones with high affinity to target FXIIa can be screened by iterative binding of phage to target FXIIa, wherein the target FXIIa is bound to a solid support (e.g., beads for solution panning or mammalian cells for cell panning), followed by removal of unbound phage, and elution of specific binding phage. Subsequently, the eluted bound phage clones are used to infect suitable host cells, such as E.coli XL1-Blue, for expression and purification. Multiple rounds of panning (e.g., 2, 3, 4, 5, 6 or more rounds), such as solution panning, cell panning or a combination of the two, can be used to enrich for phage clones that specifically bind to FXIIa. The specific binding of the enriched phage clones to the target FXIIa can be detected by any method known in the art, including, for example, ELISA and FACS.

[0372] Another method for screening antibody libraries is to display proteins on the surface of yeast cells. Wittrup et al. (U.S. Pat. Nos. 6,699,658 and 6,696,251) developed a method for displaying libraries in yeast cells. In this yeast display system, one component includes a yeast lectin protein (Aga1) anchored to the yeast cell wall, and another component includes the second subunit of the lectin protein Aga2, which can be displayed on the surface of yeast cells by binding to the Aga1 protein through a disulfide bond. The Aga1 protein is expressed by integrating the Aga1 gene into the yeast chromosome. The single-chain variable fragment (scFv) library is fused to the Aga2 gene in the yeast display plasmid, and after transformation, the library can be retained in the yeast due to the presence of an additional nutritional marker. Both Aga1 and Aga2 proteins are expressed under the control of a galactose-inducible promoter.

[0373] Human antibody V gene library (V H and V K The fragments were obtained by PCR using a set of degenerate primers (Sblattero, D. and Bradbury, A. Immunotechnology 3, 271-278 1998). The PCR templates were derived from commercially available RNA or cDNA, including PBMC, spleen, lymph node, bone marrow and tonsil. H and V K After the PCR libraries were combined, they were assembled into scFv format by overlap extension PCR (Sheets, MD et al, Proc. Natl. Acad. Sci. USA 95, 6157-6162 1998). To construct a yeast scFv display library, the resulting scFv PCR products were cloned into a yeast display plasmid in yeast by homologous recombination.

[0374] (Chao, G, et al, Nat Protoc. 2006; 1(2):755-68. Miller KD, et al. CurrentProtocols in Cytometry 4.7.1-4.7.30, 2008).

[0375] Anti-FXIIa antibodies can be screened using a mammalian cell display system, in which the antibody portion is displayed on the cell surface and antibodies that specifically target FXIIa are isolated by an antigen-directed screening method (as described in US patent No. 7,732,195B2). A Chinese hamster ovary (CHO) cell library displaying a large number of human IgG antibody genes can be established and used to find clones expressing high-affinity antibody genes. Another display system has been developed that allows the same protein to be displayed and secreted on the cell surface simultaneously through alternative splicing, in which the displayed protein phenotype remains associated with the genotype, allowing the secreted soluble antibody to be characterized in both biophysical and cell function-based analyses. This method overcomes many of the limitations of previous mammalian cell displays and is capable of directly screening and maturing full-length, glycosylated IgGs in the form of antibodies (Peter M. Bowers, et al, Methods 2014, 65: 44-56). Transient expression systems are suitable for a single round of antigen selection before antibody gene recovery and are therefore most useful for selecting antibodies from smaller libraries. Stable exosome vectors provide an attractive option. Exosome vectors can be efficiently transfected and stably maintained at low copy numbers, allowing multiple rounds of panning and the resolution of more complex antibody repertoires.

[0376] The IgG library was constructed based on the ligation of germline sequence V gene segments isolated from a group of human donors and rearranged (D)J regions. RNA collected from 2000 human blood samples was reverse transcribed into cDNA and the V H and V K Specific primers amplify V H and V K The fragment was purified by gel extraction. H and V K The fragments were subcloned into display vectors containing IgG1 or K constant regions, and then electroporated or transduced into 293T cells to prepare IgG libraries. H and V K To generate scFv, which is then subcloned into a display vector and electroporated or transduced into 293T cells. As is well known, IgG libraries are constructed based on germline sequence V gene segments and rearranged (D)J regions isolated from a group of donors, which can be mice, rats, rabbits or monkeys.

[0377] Monoclonal antibodies can also be prepared by recombinant DNA methods, such as described in US Patent No. 4,816,567. The DNA encoding the monoclonal antibodies described in the present application can be easily isolated and sequenced by conventional methods (e.g., by oligonucleotide probes that can specifically bind to the light and heavy chain genes encoding mouse antibodies). The hybridoma cells described above or the FXIIa-specific phage clones of the present application can be used as the source of such DNA. After separation, the DNA can be placed in an expression vector, and then the vector can be transfected into a host cell, such as a monkey COS cell, a Chinese hamster ovary carcinoma (CHO) cell, or a myeloma cell that does not produce immunoglobulins, to obtain a monoclonal antibody synthesized in a recombinant host cell. The DNA can also be modified, such as replacing the human heavy and light chain constant regions with coding sequences and / or replacing homologous non-human sequences with framework regions (US Patent No. 4,816,567; Morrison et al., supra), or by covalently linking the coding sequence of an immunoglobulin to all or part of the coding sequence of a non-immunoglobulin polypeptide. This non-immunoglobulin polypeptide can replace the constant region of the antibody in the present application, or can replace one antigen binding site in the variable domain of the antibody in the present application to form a chimeric bivalent antibody.

[0378] The antibody can be a monovalent antibody. Methods for preparing monovalent antibodies are known in the art. For example, a recombinant expression method involving immunoglobulin light chains and modified heavy chains. The heavy chains are usually truncated at any position in the Fc region to prevent the heavy chains from cross-linking with each other. Alternatively, the relevant cysteine ​​residues are replaced by other amino acid residues or are deleted to prevent cross-linking.

[0379] In vitro methods are also suitable for preparing monovalent antibodies. Digestion of antibodies to produce antibody fragments, particularly Fab fragments, can be accomplished using any method known in the art.

[0380] The antibody variable domains with the desired binding specificity (antibody-antigen binding site) can be fused to an immunoglobulin constant region. Preferably, the fusion is performed with an immunoglobulin heavy chain constant region, which includes at least a portion of the hinge, CH2 and CH3 regions. In some embodiments, the first heavy chain constant region (CH1) containing the necessary sites for light chain binding is present in at least one fusion. The DNA encoding the immunoglobulin heavy chain fusion, if desired, may also include DNA encoding the immunoglobulin light chain, is inserted into an independent expression vector, and co-transfected into a suitable host organism.

[0381] Fully human and humanized antibodies

[0382] The anti-FXIIa antibody (such as a full-length anti-FXIIa antibody) can be a fully human antibody or a humanized antibody. The humanized form of a non-human (such as a mouse) antibody portion is a chimeric immunoglobulin, an immunoglobulin chain, or a fragment thereof (such as Fv, Fab, Fab', F(ab')2, scFv, or other antigen-binding subsequences of an antibody), which generally includes a minimum sequence derived from a non-human immunoglobulin. Humanized antibodies include human immunoglobulins, immunoglobulin chains, or fragments thereof (receptor antibodies), wherein the residues of the receptor CDR are replaced by non-human (donor antibody) CDR residues having the desired specificity, affinity, and performance, such as mouse, rat, or rabbit CDR. In some embodiments, human immunoglobulin Fv framework region residues are replaced by corresponding non-human residues. Humanized antibodies may also include amino acid residues that are neither in the receptor antibody nor in the introduced CDR or framework region sequences. Generally, a humanized antibody comprises at least one, and typically two, variable domains, in which all or substantially all CDR regions correspond to those of a non-human immunoglobulin and all or substantially all framework regions are human immunoglobulin consensus sequences.

[0383] Typically, a humanized antibody contains one or more amino acid residues introduced from a non-human source. Those non-human amino acid residues are generally referred to as "imported" residues, usually from "imported" variable domains. According to some embodiments, humanization can be performed substantially according to the following method of Winter and his colleagues (Jones et al., Nature, 321: 522-525 (1986); Riechmann et al., Nature, 332: 323-327 (1988); Verhoeyen et al., Science, 239: 1534-1536 (1988)), by replacing the corresponding sequence of a human antibody with rodent CDRs or CDR sequences. Therefore, this "humanized" antibody portion (US Patent No. 4,816,567), which is substantially less than a complete human antibody, has its variable domains replaced by corresponding sequences from non-human sources. In practice, the humanized antibody portion is a typical human antibody portion in which some CDR residues and possibly some framework region residues are substituted by residues from analogous sites in rodent antibodies.

[0384] Fully human antibodies are an alternative to humanization. For example, transgenic animals (e.g., mice) that can produce a complete library of fully human antibodies after immunization without producing endogenous immunoglobulins can now be prepared. For example, it has been reported that homozygous deletion of the antibody heavy chain joining region (JH) gene in chimeric and germline mutant mice completely inhibits the production of endogenous antibodies. Transferring the human germline immunoglobulin gene array into such germline mutant mice can produce human antibodies under antigen stimulation, see, for example, akobovits et al., PNAS USA, 90: 2551 (1993); Jakobovits et al., Nature, 362: 255-258 (1993); Bruggemann et al., Year in Immunol., 7: 33 (1993); US Patent Nos. 5,545,806, 5,569,825, 5,591,669, 5,545,807; and WO 97 / 17852. Alternatively, fully human antibodies can be prepared by introducing human immunoglobulin loci into transgenic animals (e.g., mice in which endogenous immunoglobulin genes have been partially or completely silenced). After antigen stimulation, it can be found that the production of fully human antibodies is very similar to its production in humans in all aspects, including gene rearrangement, assembly, and antibody libraries. This method is described in, for example, US Patent Nos. 5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425; and 5,661,016, and Marks et al., Bio / Technology, 10:779-783 (1992); Lonberg et al., Nature, 368:856-859 (1994); Morrison, Nature, 368:812-813 (1994); Fishwild et al., Nature Biotechnology, 14:845-851 (1996); Neuberger, Nature Biotechnology, 14:826 (1996); Lonberg and Described in Huszar, Intern. Rev. Immunol., 13:65-93 (1995).

[0385] Fully human antibodies can also be produced by in vitro activated B cells (see US Patents 5,567,610 and 5,229,275) or by using various techniques known in the art, including phage display libraries. Hoogenboom and Winter, J. Mol. Biol., 227:381 (1991); Marks et al., J. Mol. Biol., 222:581 (1991). The techniques of Cole et al. and Boerner et al. can also be used to prepare fully human monoclonal antibodies. See Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p.77 (1985) and Boerner et al., J. Immunol., 147 (1): 86-95 (1991).

[0386] Anti-FXIIa antibody variants

[0387] In some embodiments, the amino acid sequences of anti-FXIIa antibody variants (e.g., full-length anti-FXIIa antibodies) provided herein are also under consideration. For example, it may be necessary to improve the binding affinity and / or other biological activities of the antibody. The amino acid sequence of the antibody variant can be prepared by introducing appropriate modifications into the nucleotide sequence encoding the antibody or by peptide synthesis. Such modifications include, for example, deletions and / or insertions and / or substitutions of residues in the antibody amino acid sequence. The final construction can be completed by any combination of amino acid residue deletions, insertions and substitutions to give it the desired characteristics. For example, antigen binding.

[0388] In some embodiments, anti-FXIIa antibody variants having one or more amino acid substitutions are provided. The target sites of the substitution mutations include hypervariable regions (HVRs) and framework regions (FRs). Amino acid substitutions can be introduced into the target antibody, and the product of the desired activity can be screened, for example, improved biological activity, maintaining / improving antigen binding ability, reduced immunogenicity, or improved ADCC or CDC.

[0389] Conservative substitutions are shown in Table 4 below.

[0390] Table 4 Conservative substitutions

[0391] Original residue Exemplary substitutions Preferred substitution Ala(A) Val; Leu; Ile Val Arg(R) Lys; Gln; Asn Lys Asn(N) Gln; His; Asp, Lys; Arg Gln Asp(D) Glu; Asn Glu Cys(C) Ser; Ala Ser Gln(Q) Asn; Glu Asn Glu(E) Asp; Gln Asp Gly(G) Ala Ala His(H) Asn; Gln; Lys; Arg Arg Ile(I) Leu; Val; Met; Ala; Phe; Norleucine Leu Leu(L) Norleucine;Ile;Val;Met;Ala;Phe Ile Lys(K) Arg; Gln; Asn Arg Met(M) Leu; Phe; Ile Leu Phe(F) Trp; Leu; Val; Ile; Ala; Tyr Tyr Pro(P) Ala Ala Ser(S) Thr Thr Thr(T) Val; Ser Ser Trp(W) Tyr; Phe Tyr Tyr(Y) Trp; Phe; Thr; Ser Phe Val(V) Ile; Leu; Met; Phe; Ala; Norleucine Leu

[0392] Amino acids are divided into different categories based on the properties of their side chains:

[0393] a. Hydrophobic amino acids: Norleucine, Met, Ala, Val, Leu, Ile;

[0394] b. Neutral hydrophilic amino acids: cysteine ​​Cys, serine Ser, threonine Thr, asparagine Asn, glutamine Gln;

[0395] c. Acidic amino acids: Aspartic acid Asp, glutamic acid Glu;

[0396] d. Basic amino acids: histidine His, lysine Lys, arginine Arg;

[0397] e. Contains amino acids that affect the chain direction: glycine Gly, proline Pro;

[0398] f. Aromatic amino acids: tryptophan Trp, tyrosine Tyr, phenylalanine Phe.

[0399] Non-conservative amino acid substitutions include substitutions of one species for another.

[0400] An exemplary substitution variant is an affinity-matured antibody, which can be conveniently produced using, for example, affinity maturation techniques based on phage display. In short, one or more CDR residues are mutated, the variant antibody portion is displayed on a phage, and variants with specific biological activity (e.g., based on the cleavage inhibition experiment of the FXIIa enzyme active substrate S2302 or the biological activity of binding affinity) are screened. Changes (e.g., substitutions) can be made in the HVRs region to obtain improved biological activity based on the cleavage inhibition experiment of the FXIIa enzyme active substrate S2302 or the binding affinity. Changes can be made in the "hotspots" of the HVR, i.e., residues encoded by codons that undergo high-frequency mutations during somatic maturation (see, e.g., Chowdhury, Methods Mol. Biol. 207: 179-196 (2008)), and / or at specific determinant residues (SDRs), and the resulting variant V is detected. H and V L Methods for constructing and reselecting affinity maturation from secondary libraries have been described in some literature, for example, Hoogenboom et al. in Methods in Molecular Biology 178: 1-37 (O'Brien et al., ed., Human Press, Totowa, NJ, (2001)).

[0401] In some affinity maturation embodiments, diversity is introduced into the variable genes selected for affinity maturation by any of a variety of methods (e.g., error-prone PCR, chain shuffling, or oligonucleotide directed mutagenesis). A secondary library is then created. The library is screened to identify antibody variants with the desired affinity. Another method for introducing diversity includes HVR-mediated approaches, in which several HVR residues (e.g., 4-6 residues at a time) are randomized. HVR residues involved in antigen binding are specifically identified, for example, using alanine scanning mutagenesis or modeling. Typically, CDR-H3 and CDR-L3 regions are particularly key targets.

[0402] In some embodiments, substitutions, insertions or deletions may occur within one or more HVRs, as long as such changes do not substantially reduce the ability of the antibody to bind antigen. For example, conservative changes (e.g., conservative substitutions provided herein) that do not substantially reduce binding affinity may be produced in HVRs. These changes may occur outside of HVR "hot spots" or SDRs regions. In some embodiments, the variant V provided above H and V L Sequences, each HVR is either unchanged or contains no more than 1, 2 or 3 amino acid substitutions.

[0403] A useful method for identifying amino acid residues or regions in antibodies that can be targeted for mutation is called "alanine scanning mutagenesis", as described in Cunningham and Wells (1989) Science, 244: 1081-1085. In this method, one or a group of target residues (e.g., charged residues such as arginine, aspartic acid, histidine, lysine and glutamic acid) are replaced by neutral or negatively charged amino acids (e.g., alanine or glutamic acid) to determine whether the antibody-antigen interaction is affected. Substitutions can be further introduced at the position of the amino acid to demonstrate that the position is functionally sensitive to the initial substitution. Alternatively or additionally, the contact sites between the antibody and the antigen are identified by the crystal structure of the antigen-antibody complex. These contact site residues and adjacent residues can be targeted or eliminated as substitution candidates. Variants are screened to determine whether they have the desired properties.

[0404] Insertions of amino acid sequences include fusions at the amino and / or carboxyl termini ranging in length from 1 residue to polypeptides containing 100 or more residues, and also include insertions of 1 or more amino acid residues within a sequence. Examples of terminal insertions include antibodies with a methionyl residue at the N-terminus. Other insertion variants of antibody molecules include fusions of an enzyme (e.g., ADEPT) or a polypeptide that increases the serum half-life of the antibody molecule at the N-terminus or C-terminus.

[0405] Fc region variants

[0406] In some embodiments, one or more amino acid modifications are introduced into the Fc region of an antibody described herein (e.g., a full-length anti-FXIIa antibody or an anti-FXIIa antibody fusion protein) to produce an Fc region variant. In some embodiments, the Fc region variant has enhanced ADCC potency, typically associated with receptors that bind to Fc (FcRs). In some embodiments, the Fc region variant has reduced ADCC potency. There are many examples of changes or mutations in the Fc sequence that affect its potency, for example, WO 00 / 42072 and Shields et al. J Biol. Chem. 9 (2): 6591-6604 (2001) describe antibody variants with enhanced or reduced binding to FcRs. The contents of these publications are incorporated herein by reference.

[0407] Antibody-dependent cell-mediated cytotoxicity (ADCC) is the mechanism of action of therapeutic antibodies against tumor cells. ADCC is a cell-mediated immune defense in which effector cells of the immune system actively lyse target cells (e.g., cancer cells) when antigens on the surface of the target cell membrane are bound by specific antibodies (e.g., anti-FXIIa antibodies). Usually the ADCC effect involves NK cells activated by antibodies. NK cells express the Fc receptor CD16. This receptor recognizes and binds to the Fc portion of antibody molecules bound to the surface of target cells. The most common Fc receptors on the surface of NK cells are CD16 or FcγRIII. The binding of Fc receptors to the Fc region of antibodies leads to the activation of NK cells, the release of cell lytic granules, and subsequent apoptosis of target cells. The killing effect of ADCC on tumor cells can be determined by specific experiments of NK-92 cells transfected with high-affinity FcR. The results are compared with wild-type NK-92 that do not express FcR.

[0408] In some embodiments, the present application also provides anti-FXIIa antibody variants (e.g., full-length anti-FXIIa antibody variants) comprising an Fc region with some but not all effector functions, so that it has an extended half-life in vivo, but a specific effector function (e.g., CDC or ADCC) is non-essential or harmful, and such anti-FXIIa antibodies become ideal candidates for the present application. The reduction / elimination of CDC and / or ADCC activity is confirmed by performing cytotoxicity assays in vitro and / or in vivo. For example, an Fc receptor (FcR) binding assay is used to confirm that the antibody lacks FcγR binding ability (and therefore may lack ADCC activity) but still retains FcRn binding ability. Among the main cells that mediate ADCC, NK cells express only FcγRIII, while monocytes express FcγRI, FcγRII, and FcγRIII. The expression of FcR on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet Annu. Rev. Immunol. 9: 457-492 (1991). Non-limiting examples of in vitro assessment of ADCC activity of target molecules are described in US Pat. No. 5,500,362 (see, e.g., Hellstrom, I. et al. Proc. Nat'l Acad. Sci. USA 83:7059-7063 (1986) and Hellstrom, I et al., Proc. Nat'l Acad. Sci. USA 82:1499-1502 (1985); US Pat. No. 5,821,337 (see Bruggemann, M. et al., J. Exp. Med. 166:1351-1361 (1987)). Alternatively, non-radioactive detection methods can be used (see, e.g., ACTI TM Flow cytometry nonradioactive cytotoxicity assay (Cell Technology, Inc. Mountain View, Calif.) and CYTOTOX 96 TMNon-radioactive cytotoxicity assays (Promega, Madison, Wis.). Effector cells used in such assays include peripheral blood mononuclear cells (PBMC) and natural killer cells (NK). Alternatively, ADCC activity of the target molecule is tested in vivo, for example, in an animal model as described in Clynes et al. Proc. Nat'l Acad. Sci. USA 95:652-656 (1998). A C1q binding assay can also be performed to confirm that the antibody cannot bind to C1q and thus lacks CDC activity. See, for example, C1q and C3c binding ELISAs in WO 2006 / 029879 and WO 2005 / 100402. To assess complement activation, a CDC assay can be performed (see, e.g., Gazzano-Santoro et al., J. Immunol. Methods 202: 163 (1996); Cr...

Claims

1. An isolated anti-FXIIa antibody, wherein the anti-FXIIa antibody comprises: (i)V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 10, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 22; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO:34, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:48, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO:56; (ii) V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 11, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 23; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO:35, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:49, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO:57; (iii)V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 2, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 12, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 24; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO:36, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:50, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO:58; (iv)V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 3, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 13, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 25; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO:37, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:51, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO:59; (v)V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO:4, HC-CDR2 comprising the amino acid sequence of SEQ ID NO:14, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO:26; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO:37, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:51, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO:60; (vi)V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 3, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 13, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 25; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO:37, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:51, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO:61; (vii) V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 2, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 12, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 24; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO:38, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:50, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO:62; (viii) V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 3, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 13, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 25; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO:39, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:52, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO:63; (ix)V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 10, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 27; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO:40, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:53, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO:64; (x)V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO:5, HC-CDR2 comprising the amino acid sequence of SEQ ID NO:15, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO:28; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO:41, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:50, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO:65; (xi)V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 6, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 16, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 29; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO:42, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:54, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO:66; (xii)V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 6, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 17, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 30; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO:43, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:50, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO:67; (xiii)V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO:5, HC-CDR2 comprising the amino acid sequence of SEQ ID NO:15, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO:28; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO:44, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:50, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO:68; (xiv)V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO:7, HC-CDR2 comprising the amino acid sequence of SEQ ID NO:18, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO:31; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO:45, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:55, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO:69; (xv)V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 8, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 19, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 28; and V L , the V L comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO:46, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:50, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO:70; (xvi)V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO:9, HC-CDR2 comprising the amino acid sequence of SEQ ID NO:20, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO:32; and V L , the V L comprising: a LC-CDR1 comprising the amino acid sequence of SEQ ID NO:47, a LC-CDR2 comprising the amino acid sequence of SEQ ID NO:51, and a LC-CDR3 comprising the amino acid sequence of SEQ ID NO:71; or (xvii)V H , the V H comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 3, HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 21, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 33; and V L , the V L It comprises: LC-CDR1, which comprises the amino acid sequence of SEQ ID NO:37, LC-CDR2, which comprises the amino acid sequence of SEQ ID NO:51, and LC-CDR3, which comprises the amino acid sequence of SEQ ID NO:

72.

2. The isolated anti-FXIIa antibody according to claim 1, comprising: (i)V H , comprising the amino acid sequence shown in SEQ ID NO: 73 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO: 73; and V L , comprising the amino acid sequence shown in SEQ ID NO:90 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO:90; (ii) V H , comprising the amino acid sequence shown in SEQ ID NO: 74 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO: 74; and V L , comprising the amino acid sequence shown in SEQ ID NO:91 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO:91; (iii)V H , comprising the amino acid sequence shown in SEQ ID NO: 75 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO: 75; and V L , comprising the amino acid sequence shown in SEQ ID NO:92 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO:92; (iv)V H , comprising the amino acid sequence shown in SEQ ID NO: 76 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO: 76; and V L , comprising the amino acid sequence shown in SEQ ID NO:93 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO:93; (v)V H , comprising the amino acid sequence shown in SEQ ID NO: 77 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO: 77; and V L , comprising the amino acid sequence shown in SEQ ID NO:94 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO:94; (vi)V H , comprising the amino acid sequence shown in SEQ ID NO: 78 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO: 78; and V L , comprising the amino acid sequence shown in SEQ ID NO:95 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO:95; (vii) V H , comprising the amino acid sequence shown in SEQ ID NO: 79 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO: 79; and V L , comprising the amino acid sequence shown in SEQ ID NO:96 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO:96; (viii)V H , comprising the amino acid sequence shown in SEQ ID NO: 80 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO: 80; and V L , comprising the amino acid sequence shown in SEQ ID NO:97 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO:97; (ix)V H , comprising the amino acid sequence shown in SEQ ID NO:81 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO:81; and V L , comprising the amino acid sequence shown in SEQ ID NO:98 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO:98; (x)V H , comprising the amino acid sequence shown in SEQ ID NO:82 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO:82; and V L , comprising the amino acid sequence shown in SEQ ID NO:99 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO:99; (xi)V H , comprising the amino acid sequence shown in SEQ ID NO:83 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO:83; and V L , comprising the amino acid sequence shown in SEQ ID NO: 100 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO: 100; (xii)V H , comprising the amino acid sequence shown in SEQ ID NO:84 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO:84; and V L , comprising the amino acid sequence shown in SEQ ID NO: 101 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO: 101; (xiii)V H , which comprises the amino acid sequence shown in SEQ ID NO:85 or a variant thereof, wherein the variant is identical to SEQ ID NO:85 The amino acid sequences shown have at least 80% sequence identity; and V L , comprising the amino acid sequence shown in SEQ ID NO: 102 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO: 102; (xiv)V H , which comprises the amino acid sequence shown in SEQ ID NO:86 or a variant thereof, wherein the variant is identical to SEQ ID NO:86 The amino acid sequences shown have at least 80% sequence identity; and V L , comprising the amino acid sequence shown in SEQ ID NO: 103 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO: 103; (xv)V H , which comprises the amino acid sequence shown in SEQ ID NO:87 or a variant thereof, wherein the variant is identical to SEQ ID NO:87 The amino acid sequences shown have at least 80% sequence identity; and V L , comprising the amino acid sequence shown in SEQ ID NO: 104 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO: 104; (xvi)V H , which comprises the amino acid sequence shown in SEQ ID NO:88 or a variant thereof, wherein the variant is identical to SEQ ID NO:88 The amino acid sequences shown have at least 80% sequence identity; and V L , which comprises the amino acid sequence shown in SEQ ID NO: 105 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO: 105; or (xvii)V H , comprising the amino acid sequence shown in SEQ ID NO:89 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO:89; and V L , which comprises the amino acid sequence shown in SEQ ID NO:106 or a variant thereof, wherein the variant has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO:

106. 3 . The isolated anti-FXIIa antibody according to any one of claims 1 - 2 , wherein the anti-FXIIa antibody binds to human FXIIa with a Kd value of 0.1 pM to 1 nM. 4 . The isolated anti-FXIIa antibody according to any one of claims 1 to 3 , wherein the anti-FXIIa antibody comprises an Fc fragment.

5. The isolated anti-FXIIa antibody according to claim 4, wherein the anti-FXIIa antibody is a full-length IgA, IgD, IgE, IgG or IgM antibody.

6. The isolated anti-FXIIa antibody according to claim 5, wherein the anti-FXIIa antibody is a full-length IgG1, IgG2, IgG3 or IgG4 antibody.

7. The isolated anti-FXIIa antibody according to any one of claims 1 to 6, wherein the anti-FXIIa antibody is a chimeric, human or humanized antibody.

8. An isolated anti-FXIIa antibody according to any one of claims 1 to 3, wherein the anti-FXIIa antibody is an antigen-binding fragment selected from the group consisting of Fab, Fab', F(ab)'2, Fab'-SH, single-chain Fv (scFv), Fv fragment, dAb, Fd, nanobody, diabody and linear antibody.

9. An isolated nucleic acid molecule encoding the anti-FXIIa antibody of any one of claims 1-8.

10. A vector comprising the nucleic acid molecule of claim 9. 11 . An isolated host cell comprising the anti-FXIIa antibody of any one of claims 1 to 8 , the nucleic acid molecule of claim 9 , or the vector of claim 10 .

12. A method for preparing an anti-FXIIa antibody, comprising: a) culturing the host cell of claim 11 under conditions effective for expressing the anti-FXIIa antibody; and b) obtaining the expressed anti-FXIIa antibody from the host cells.

13. A pharmaceutical composition comprising the anti-FXIIa antibody of any one of claims 1 to 8, the nucleic acid molecule of claim 9, the vector of claim 10, the isolated host cell of claim 11 or the antibody prepared by the method of claim 12, and a pharmaceutically acceptable carrier.

14. Use of the antibody of any one of claims 1 to 8, the nucleic acid molecule of claim 9, the vector of claim 10, the host cell of claim 11, the antibody prepared by the method of claim 12, or the pharmaceutical composition of claim 13 in the preparation of a medicament for treating a disease or condition in an individual in need thereof, wherein the disease or condition is a disease and / or condition caused by dysregulation of the FXIIa signaling pathway, such as thrombosis, diseases associated with FXII / FXIIa-induced kinin formation, diseases associated with FXII / FXIIa-induced complement activation, diseases associated with the contact activation system, and diseases associated with inflammation.

15. The method of claim 14, wherein the disease or condition is selected from the group consisting of venous, arterial or capillary thrombosis, intracardiac thrombosis, thrombosis during and / or after contacting the blood of a human or animal subject with an artificial surface, thromboembolism, atherosclerosis, interstitial lung disease, inflammation, neuroinflammatory diseases, neurotraumatic diseases, traumatic brain injury, complement activation, fibrinolysis, angiogenesis, hereditary angioedema (HAE), bacterial pulmonary infection, trypanosoma infection, hypotensive shock, pancreatitis, chagas disease, arthritis, arthritis, disseminated intravascular coagulation and sepsis, macular edema, diabetic retinopathy, hypertensive retinopathy, age-related macular degeneration, retinal vein occlusion, organ ischemia, distal ischemia-reperfusion injury (IRI), chronic kidney disease, renal fibrosis, multiple sclerosis.

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